CDK2/4/6 Inhibitors

ABSTRACT

This invention relates to compounds of general Formula (I)and pharmaceutically acceptable salts thereof, in which R1, R2, R2A, R2B, R3, R4, R5A, R5B, R6, R7, R8, R9, p, q and r are as defined herein, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. patentapplication Ser. No. 17/005,233, filed Aug. 27, 2020, now allowed, whichis a divisional application of U.S. patent application Ser. No.16/251,032, filed Jan. 17, 2019, now U.S. Pat. No. 10,800,783, which isa continuation of U.S. patent application Ser. No. 15/664,265, filedJul. 31, 2017, now U.S. Pat. No. 10,233,188, which claims the benefit ofpriority to U.S. Provisional Application No. 62/371,602, filed on Aug.15, 2016, and to U.S. Provisional Application No. 62/533,347, filed onJul. 17, 2017, each of which is incorporated by reference herein in itsentirety.

REFERENCE TO SEQUENCE LISTING

This application is being filed electronically via EFS-Web and includesan electronically submitted sequence listing in .txt format. The .txtfile contains a sequence listing entitled “PC72302CSEQLISTING_ST25.txt”created on May 11, 2022 and having a size of 2 KB. The sequence listingcontained in this .txt file is part of the specification and is hereinincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds of Formulae (I) to (VII), andtheir pharmaceutically acceptable salts, to pharmaceutical compositionscomprising such compounds and salts, and to the uses thereof. Thecompounds, salts and compositions of the present invention are usefulfor treating or ameliorating abnormal cell proliferative disorders, suchas cancer.

BACKGROUND

Cyclin-dependent kinases (CDKs) are important cellular enzymes thatperform essential functions in regulating eukaryotic cell division andproliferation. The cyclin-dependent kinase catalytic units are activatedby regulatory subunits known as cyclins. At least sixteen mammaliancyclins have been identified (Johnson D G, Walker C L. Cyclins and CellCycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312).Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclinD/CDK6, and likely other heterodynes are important regulators of cellcycle progression. Additional functions of cyclin/CDK heterodynesinclude regulation of transcription, DNA repair, differentiation andapoptosis (Morgan D O. Cyclin-dependent kinases: engines, clocks, andmicroprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).

Cyclin-dependent kinase inhibitors have been demonstrated to be usefulin treating cancer. Increased activity or temporally abnormal activationof cyclin-dependent kinases has been shown to result in the developmentof human tumors, and human tumor development is commonly associated withalterations in either the CDK proteins themselves or their regulators(Cordon-Cardo C. Mutations of cell cycle regulators: biological andclinical implications for human neoplasia. Am. J. Pathol. (1995)147:545-560; Karp J E, Broder S. Molecular foundations of cancer: newtargets for intervention. Nat. Med. (1995) 1:309-320; Hall M, Peters G.Genetic alterations of cyclins, cyclin-dependent kinases, and Cdkinhibitors in human cancer. Adv. Cancer Res. (1996) 68:67-108).Amplifications of the regulatory subunits of CDKs and cyclins, andmutation, gene deletion, or transcriptional silencing of endogenous CDKinhibitors have also been reported (Smalley et al. Identification of anovel subgroup of melanomas with KIT/cyclin-dependent kinase-4overexpression. Cancer Res (2008) 68: 5743-52).

Clinical trials for the CDK4/6 inhibitors palbociclib, ribociclib andabemaciclib are ongoing for breast and other cancers, as single agentsor in combination with other therapeutics. Palbociclib and ribociclibhave been approved for treatment of hormone receptor (HR)-positive,human epidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer in combination with aromatase inhibitors inpost-menopausal women, and for palbociclib, in combination withfulvestrant after disease progression following endocrine therapy,(O'Leary et al. Treating cancer with selective CDK4/6 inhibitors. NatureReviews (2016) 13:417-430). While CDK4/6 inhibitors have shownsignificant clinical efficacy in ER-positive metastatic breast cancer,as with other kinases their effects may be limited over time by thedevelopment of primary or acquired resistance.

Overexpression of CDK2 is associated with abnormal regulation ofcell-cycle. The cyclin E/CDK2 complex plays and important role inregulation of the G1/S transition, histone biosynthesis and centrosomeduplication. Progressive phosphorylation of Rb by cyclin D/Cdk4/6 andcyclin E/Cdk2 releases the G1 transcription factor, E2F, and promotesS-phase entry. Activation of cyclin A/CDK2 during early S-phase promotesphosphorylation of endogenous substrates that permit DNA replication andinactivation of E2F, for S-phase completion. (Asghar et al. The historyand future of targeting cyclin-dependent kinases in cancer therapy, Nat.Rev. Drug. Discov. 2015; 14(2): 130-146).

Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed incancer. Cyclin E amplification or overexpression has long beenassociated with poor outcomes in breast cancer. (Keyomarsi et al.,Cyclin E and survival in patients with breast cancer. N Engl J Med.(2002) 347:1566-75). Cyclin E2 (CCNE2) overexpression is associated withendocrine resistance in breast cancer cells and CDK2 inhibition has beenreported to restore sensitivity to tamoxifen or CDK4 inhibitors intamoxifen-resistant and CCNE2 overexpressing cells. (Caldon et al.,Cyclin E2 overexpression is associated with endocrine resistance but notinsensitivity to CDK2 inhibition in human breast cancer cells. MolCancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Early Adaptationand Acquired Resistance to CDK4/6 Inhibition in EstrogenReceptor-Positive Breast Cancer, Cancer Res. (2016) 76: 2301-2313).Cyclin E amplification also reportedly contributes to trastuzumabresistance in HER2+ breast cancer. (Scaltriti et al. Cyclin Eamplification/overexpression is a mechanism of trastuzumab resistance inHER2+ breast cancer patients, Proc Natl Acad Sci. (2011) 108: 3761-6).Cyclin E overexpression has also been reported to play a role inbasal-like and triple negative breast cancer (TNBC), as well asinflammatory breast cancer. (Elsawaf & Sinn, Triple Negative BreastCancer: Clinical and Histological Correlations, Breast Care (2011)6:273-278; Alexander et al., Cyclin E overexpression as a biomarker forcombination treatment strategies in inflammatory breast cancer,Oncotarget (2017) 8: 14897-14911.)

Amplification or overexpression of cyclin E1 (CCNE1) is also associatedwith poor outcomes in ovarian, gastric, endometrial and other cancers.(Nakayama et al., Gene amplification CCNE1 is related to poor survivaland potential therapeutic target in ovarian cancer, Cancer (2010) 116:2621-34; Etemadmoghadam et al., Resistance to CDK2 Inhibitors IsAssociated with Selection of Polyploid Cells in CCNE1-Amplified OvarianCancer, Clin Cancer Res (2013) 19: 5960-71; Au-Yeung et al., SelectiveTargeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer byCyclin-Dependent Kinase 2 and AKT Inhibition, Clin. Cancer Res. (2017)23:1862-1874; Ayhan et al., CCNE1 copy-number gain and overexpressionidentify ovarian clear cell carcinoma with a poor prognosis, ModernPathology (2017) 30: 297-303; Ooi et al., Gene amplification of CCNE1,CCND1, and CDK6 in gastric cancers detected by multiplexligation-dependent probe amplification and fluorescence in situhybridization, Hum Pathol. (2017) 61: 58-67; Noske et al., Detection ofCCNE1/URI (19q12) amplification by in situ hybridisation is common inhigh grade and type II endometrial cancer, Oncotarget (2017) 8:14794-14805).

The small molecule inhibitor, dinaciclib (MK-7965) inhibits CDK1, CDK2,CDK5 and CDK9 and is currently in clinical development for breast andhematological cancers. Seliciclib (roscovitine or CYC202), whichinhibits CDK2, CDK7 and CDK9, is being investigated for treatment ofadvanced solid tumors in conjunction with chemotherapy. Despitesignificant efforts, there are no approved agents targeting CDK2 todate. Cicenas et al. Highlights of the Latest Advances in Research onCDK Inhibitors. Cancers, (2014) 6:2224-2242. There remains a need todiscover CDK inhibitors having novel activity profiles, in particularthose targeting CDK2.

SUMMARY

The present invention provides, in part, compounds of Formulae (I) to(VII), and pharmaceutically acceptable salts thereof. Such compounds caninhibit the activity of CDKs, including CDK2, CDK4 and/or CDK6, therebyeffecting biological functions. Also provided are pharmaceuticalcompositions and medicaments, comprising the compounds or salts of theinvention, alone or in combination with additional anticancertherapeutic agents or palliative agents.

The present invention also provides, in part, methods for preparing thecompounds, pharmaceutically acceptable salts and compositions of theinvention, and methods of using the foregoing.

In one aspect, the invention provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A) or C₃-C₈cycloalkyl substituted by R^(5B), where said 3-10 membered heterocyclyland C₃-C₈ cycloalkyl are optionally further substituted by one or moreR⁶;

each R² is independently F, OH, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₄alkoxy or C₁-C₄ fluoroalkoxy;

R^(2A) and R^(2B) are independently H, F, OH, C₁-C₄ alkyl, C₁-C₄fluoroalkyl, C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy;

-   -   where each said C₁-C₄ alkyl and C₁-C₄ fluoroalkyl in R², R^(2A)        and R^(2B) is independently optionally substituted by OH, C₁-C₄        alkoxy or C₁-C₄ fluoroalkoxy;

R³ is H, F, Cl, NH₂, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄alkyl and C₁-C₄ fluoroalkyl are optionally substituted by OH, CN, C₁-C₄alkoxy, C₁-C₄ fluoroalkoxy, CONH₂ and COOH;

R⁴ is H, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl;

R^(5A) is SO₂R⁷, SO₂NR⁸R⁹, NHSO₂R⁷ or NHSO₂NR⁸R⁹;

R^(5B) is NHSO₂R⁷ or NHSO₂NR⁸R⁹;

each R⁶ is independently F, OH, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₄alkoxy or C₁-C₄ fluoroalkoxy;

R⁷ is C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, -L-(C₃-C₈ cycloalkyl), -L-(5-6membered heterocyclyl) or -L-(5-6 membered heteroaryl);

R⁸ and R⁹ are independently H, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, -L-(C₃-C₈cycloalkyl), -L-(5-6 membered heterocyclyl) or -L-(5-6 memberedheteroaryl); or

R⁸ and R⁹ may be taken together with the nitrogen atom to which they areattached to form a 5-6 membered heterocyclyl;

-   -   where each said C₁-C₄ alkyl and C₁-C₄ fluoroalkyl in R⁷, R⁸ and        R⁹ is optionally substituted by OH, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy or SO₂Me, and each said C₃-C₈ cycloalkyl, 5-6        membered heterocyclyl and 5-6 membered heteroaryl in R⁷, R⁸ and        R⁹ is optionally substituted by C₁-C₄ alkyl, OH, C₁-C₄ alkoxy or        C₁-C₄ fluoroalkoxy;

L is a bond or C₁-C₄ alkylene, where said C₁-C₄ alkylene is optionallysubstituted by OH, C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy;

p is 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3; and

r is 0, 1 or 2.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of any one of the formulae described herein, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient. In some embodiments, the pharmaceuticalcomposition comprises two or more pharmaceutically acceptable carriersand/or excipients.

The invention also provides therapeutic methods and uses comprisingadministering a compound of the invention, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the invention provides a method for the treatment ofabnormal cell growth, in particular cancer, in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof. Compounds of the invention may be administeredas single agents, or may be administered in combination with otheranti-cancer therapeutic agents, in particular standard of care agentsappropriate for the particular cancer.

In a further aspect, the invention provides a method for the treatmentof abnormal cell growth, in particular cancer, in a subject in needthereof, comprising administering to the subject an amount of a compoundof the invention, or a pharmaceutically acceptable salt thereof, incombination with an amount of an additional anti-cancer therapeuticagent, which amounts are together effective in treating said abnormalcell growth.

In another aspect, the invention relates to a compound of the invention,or a pharmaceutically acceptable salt thereof, for use as a medicament,in particular a medicament for treatment of cancer.

In another aspect, the invention relates to a compound of the invention,of a pharmaceutically acceptable salt thereof, for use in the treatmentof abnormal cell growth, in particular cancer, in a subject.

In a further aspect, the invention provides the use of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for thetreatment of abnormal cell growth, in particular cancer, in a subject.

In another aspect, the invention relates to a pharmaceutical compositionfor use in the treatment of abnormal cell growth in a subject in needthereof, which composition comprises a compound of the invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.

In yet another aspect, the invention provides the use of a compound ofany one of the formulae described herein, or a pharmaceuticallyacceptable salt thereof, for the preparation of a medicament for thetreatment of abnormal cell growth in a subject.

In frequent embodiments of the foregoing compounds, methods and uses,the abnormal cell growth is cancer.

In some embodiments, the methods and uses provided result in one or moreof the following effects: (1) inhibiting cancer cell proliferation, (2)inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancercells; (4) inhibiting cancer cell metastasis; or (5) inhibitingangiogenesis.

In another aspect, the invention provides a method for the treatment ofa disorder mediated by CDK2 in a subject, comprising administering tothe subject a compound of the invention, or a pharmaceuticallyacceptable salt thereof, in an amount that is effective for treatingsaid disorder, in particular cancer. In some embodiments, the disorderis cancer that is characterized by amplification or overexpression ofCCNE1 and/or CCNE2.

In another aspect, the invention provides a method for the treatment ofa disorder mediated by CDK2, CDK4 and/or CDK6 in a subject, comprisingadministering to the subject a compound of the invention, or apharmaceutically acceptable salt thereof, in an amount that is effectivefor treating said disorder, in particular cancer. In some embodiments,the disorder is cancer that is characterized by amplification oroverexpression of CCNE1 and/or CCNE2.

In some embodiments, the methods and uses described herein furthercomprise administering to the subject an amount of an additionalanticancer therapeutic agent or a palliative agent, which amounts aretogether effective in treating said abnormal cell growth. Each of theembodiments of the compounds of the present invention described belowcan be combined with one or more other embodiments of the compounds ofthe present invention described herein not inconsistent with theembodiment(s) with which it is combined.

In addition, each of the embodiments below describing the inventionenvisions within its scope the pharmaceutically acceptable salts of thecompounds of the invention. Accordingly, the phrase “or apharmaceutically acceptable salt thereof” is implicit in the descriptionof all compounds described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows cyclin E1/2 (CCNE1/2) amplification frequency by tumor type(http://oasis.pfizer.com/).

FIGS. 2A-2D show in vitro IC₅₀ data for the compound of Example 10 andpalbociclib in Ovcar3 (CCNE amplified ovarian carcinoma) Rb ELISA assayin FIG. 2A; HCC1806 (CCNE amplified breast carcinoma) Rb ELISA assay inFIG. 2B; Ovcar3 cell proliferation assay in FIG. 2C; and HCC1806 cellproliferation assay in FIG. 2D.

FIG. 3 shows tumor growth inhibition for the compound of Example 2 inOvcar3 mouse tumor xenograft model at 10 mpk PO QD, 50 mpk PO QD and 50mpk PO BID.

FIG. 4 shows tumor growth inhibition for the compound of Example 10 inHCC1806 mouse tumor xenograft model at 30 mpk PO BID, 50 mpk PO BID and75 mpk PO BID.

FIG. 5 shows the flow reactor set up for the preparation of Example 133and Example 134.

DETAILED DESCRIPTION

The present invention may be understood more readily by reference to thefollowing detailed description of the preferred embodiments of theinvention and the Examples included herein. It is to be understood thatthe terminology used herein is for the purpose of describing specificembodiments only and is not intended to be limiting. It is further to beunderstood that unless specifically defined herein, the terminology usedherein is to be given its traditional meaning as known in the relevantart.

As used herein, the singular form “a”, “an”, and “the” include pluralreferences unless indicated otherwise. For example, “a” substituentincludes one or more substituents.

The invention described herein suitably may be practiced in the absenceof any element(s) not specifically disclosed herein. Thus, for example,in each instance herein any of the terms “comprising”, “consistingessentially of”, and “consisting of” may be replaced with either of theother two terms.

“Alkyl” refers to a saturated, monovalent aliphatic hydrocarbon radicalincluding straight chain and branched chain groups having the specifiednumber of carbon atoms. Alkyl substituents typically contain 1 to 20carbon atoms (“C₁-C₂₀ alkyl”), preferably 1 to 12 carbon atoms (“C₁-C₁₂alkyl”), more preferably 1 to 8 carbon atoms (“C₁-C₈ alkyl”), or 1 to 6carbon atoms (“C₁-C₆ alkyl”), or 1 to 4 carbon atoms (“C₁-C₄ alkyl”).Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,n-heptyl, n-octyl and the like. Alkyl groups may be substituted orunsubstituted. In particular, unless otherwise specified, alkyl groupsmay be substituted by one or more halo groups, up to the total number ofhydrogen atoms present on the alkyl moiety. Thus, C₁-C₄ alkyl includeshalogenated alkyl groups, and in particular fluorinated alkyl groups,having 1 to 4 carbon atoms, e.g., trifluoromethyl or difluoroethyl(i.e., CF₃ and —CH₂CHF₂).

Alkyl groups described herein as optionally substituted may besubstituted by one or more substituent groups, which are selectedindependently unless otherwise indicated. The total number ofsubstituent groups may equal the total number of hydrogen atoms on thealkyl moiety, to the extent such substitution makes chemical sense.Optionally substituted alkyl groups typically contain from 1 to 6optional substituents, sometimes 1 to 5 optional substituents,preferably from 1 to 4 optional substituents, or more preferably from 1to 3 optional substituents.

Optional substituent groups suitable for alkyl include, but are notlimited to C₃-C₈ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl and5-12 membered heteroaryl, halo, ═O (oxo), ═S (thiono), ═N—CN, ═N—OR^(x),═NR^(x), —CN, —C(O)R^(x), —CO₂R^(x), —C(O)NR^(x)R^(y), —SR^(x),—SOR^(x), —SO₂R^(x), —SO₂NR^(x)R^(y), —NO₂, —NR^(x)R^(y),—NR^(x)C(O)R^(y), —NR^(x)C(O)NR^(x)R^(y), —NR^(x)C(O)OR^(x),—NR^(x)SO₂R^(y), —NR^(x)SO₂NR^(x)R^(y), —OR^(x), —OC(O)R^(x) and—OC(O)NR^(x)R^(y); wherein each R^(x) and R^(y) is independently H,C₁-C₈ alkyl, C₁-C₈ acyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl,3-12 membered heterocyclyl, C₆-C₁₂ aryl, or 5-12 membered heteroaryl, orR^(x) and R^(y) may be taken together with the N atom to which they areattached to form a 3-12 membered heterocyclyl or 5-12 memberedheteroaryl, each optionally containing 1, 2 or 3 additional heteroatomsselected from O, N and S(O)_(q) where q is 0-2; each R^(x) and R^(y) isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, ═O, ═S, ═N—CN, ═N—OR′, ═NR′, —CN,—C(O)R′, —CO₂R′, —C(O)NR′₂, —SOR′, —SO₂R′, —SO₂NR′₂, —NO₂, —NR′₂,—NR′C(O)R′, —NR′C(O)NR′₂, —NR′C(O)OR′, —NR′SO₂R′, —NR′SO₂NR′₂, —OR′,—OC(O)R′ and —OC(O)NR′₂, wherein each R′ is independently H, C₁-C₈alkyl, C₁-C₈ acyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, 3-12membered heterocyclyl, C₆-C₁₂ aryl, or C₅-C₁₂ heteroaryl; and whereineach said C₃-C₈ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryl and5-12 membered heteroaryl is optionally substituted as further definedherein.

Typical substituent groups on alkyl include halo, —OH, C₁-C₄ alkoxy,—O—C₆-C₁₂ aryl, —CN, ═O, —COOR^(x), —OC(O)R^(x), —C(O)NR^(x)R^(y),—NR^(x)C(O)R^(y), —NR^(x)R^(y), C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, 5-12membered heteroaryl and 3-12 membered heterocyclyl; where each R^(x) andR^(y) is independently H or C₁-C₄ alkyl, or R^(x) and R^(y) may be takentogether with the N to which they are attached form a 3-12 memberedheterocyclyl or 5-12 membered heteroaryl ring, each optionallycontaining 1, 2 or 3 additional heteroatoms selected from O, N andS(O)_(q) where q is 0-2; wherein each said C₃-C₈ cycloalkyl, C₆-C₁₂aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl isoptionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of halo, —OH, ═O, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy-C₁-C₆ alkyl, —CN,—NH₂, —NH(C₁-C₄ alkyl) and —N(C₁-C₄ alkyl)₂.

In some embodiments, alkyl is optionally substituted by one or moresubstituents, and preferably by 1 to 3 substituents, which areindependently selected from the group consisting of halo, —OH, C₁-C₄alkoxy, —O—C₆-C₁₂ aryl, —CN, ═O, —COOR^(x), —OC(O)R^(x),—C(O)NR^(x)R^(y), —NR^(x)C(O)R^(y), —NR^(x)R^(y), C₃-C₈ cycloalkyl,C₆-C₁₂ aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl;where each R^(x) and R^(y) is independently H or C₁-C₄ alkyl, or R^(x)and R^(y) may be taken together with the N to which they are attachedform a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, eachoptionally containing 1, 2 or 3 additional heteroatoms selected from O,N and S(O)_(x) where x is 0-2; and each said C₃-C₈ cycloalkyl, C₆-C₁₂aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl isoptionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of halo, —OH, ═O, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy-C₁-C₆ alkyl, —CN,—NH₂, —NH(C₁-C₄ alkyl) and —N(C₁-C₄ alkyl)₂.

In other embodiments, alkyl is optionally substituted by one or moresubstituent, and preferably by 1 to 3 substituents, independentlyselected from the group consisting of halo, —OH, C₁-C₄ alkoxy, —CN,—NR^(x)R^(y), C₃-C₈ cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₂ aryland 5-12 membered heteroaryl; where each R^(x) and R^(y) isindependently H or C₁-C₄ alkyl, or R^(x) and R^(y) may be taken togetherwith the N to which they are attached form a 3-12 membered heterocyclylor 5-12 membered heteroaryl ring, each optionally containing 1, 2 or 3additional heteroatoms selected from O, N and S(O)_(x) where x is 0-2;and where each said cycloalkyl, heterocyclyl, aryl or heteroaryl isoptionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of halo, —OH, ═O, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy-C₁-C₆ alkyl, —CN,—NH₂, —NH(C₁-C₄ alkyl) and —N(C₁-C₄ alkyl)₂.

In some instances, substituted alkyl groups are specifically named byreference to the substituent group. For example, “haloalkyl” refers toan alkyl group having the specified number of carbon atoms that issubstituted by one or more halo substituents, and typically contain 1-6carbon atoms, or preferably 1-4 carbon atoms or 1-2 carbon atoms and 1,2 or 3 halo atoms (i.e., “C₁-C₆ haloalkyl”, C₁-C₄ haloalkyl” or C₁-C₂haloalkyl”). More specifically, fluorinated alkyl groups may bespecifically referred to as fluoroalkyl groups, e.g., C₁-C₆, C₁-C₄ orC₁-C₂ fluoroalkyl groups, which are typically substituted by 1, 2 or 3fluoro atoms. Thus, a C₁-C₄ fluoroalkyl includes trifluoromethyl (—CF₃),difluoromethyl (—CF₂H), fluoromethyl (—CFH₂), difluoroethyl (—CH₂CF₂H),and the like.

Similarly, “hydroxyalkyl” refers to an alkyl group having the specifiednumber of carbon atoms that is substituted by one or more hydroxysubstituents, and typically contain 1-6 carbon atoms, preferably 1-4carbon atoms, and 1, 2 or 3 hydroxy (i.e., “C₁-C₆ hydroxyalkyl”). Thus,C₁-C₆ hydroxyalkyl includes hydroxymethyl (—CH₂OH) and 2-hydroxyethyl(—CH₂CH₂OH).

“Alkoxyalkyl” refers to an alkyl group having the specified number ofcarbon atoms that is substituted by one or more alkoxy substituents.Alkoxyalkyl groups typically contain 1-6 carbon atoms in the alkylportion and are substituted by 1, 2 or 3 C₁-C₄ alkyoxy substituents.Such groups are sometimes described herein as C₁-C₄ alkyoxy-C₁-C₆ alkyl.

“Aminoalkyl” refers to alkyl group having the specified number of carbonatoms that is substituted by one or more substituted or unsubstitutedamino groups, as such groups are further defined herein. Aminoalkylgroups typically contain 1-6 carbon atoms in the alkyl portion and aresubstituted by 1, 2 or 3 amino substituents. Thus, a C₁-C₆ aminoalkylincludes, for example, aminomethyl (—CH₂NH₂), N,N-dimethylaminoethyl(—CH₂CH₂N(CH₃)₂), 3-(N-cyclopropylamino)propyl (—CH₂CH₂CH₂NH—^(c)Pr) andN-pyrrolidinylethyl (—CH₂CH₂—N-pyrrolidinyl).

“Alkenyl” refers to an alkyl group, as defined herein, consisting of atleast two carbon atoms and at least one carbon-carbon double bond.Typically, alkenyl groups have 2 to 20 carbon atoms (“C₂-C₂₀ alkenyl”),preferably 2 to 12 carbon atoms (“C₂-C₁₂ alkenyl”), more preferably 2 to8 carbon atoms (“C₂-C₈ alkenyl”), or 2 to 6 carbon atoms (“C₂-C₆alkenyl”), or 2 to 4 carbon atoms (“C₂-C₄ alkenyl”). Representativeexamples include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups areunsubstituted or substituted by the same groups that are describedherein as suitable for alkyl.

“Alkynyl” refers to an alkyl group, as defined herein, consisting of atleast two carbon atoms and at least one carbon-carbon triple bond.Alkynyl groups have 2 to 20 carbon atoms (“C₂-C₂₀ alkynyl”), preferably2 to 12 carbon atoms (“C₂-C₁₂ alkynyl”), more preferably 2 to 8 carbonatoms (“C₂-C₈ alkynyl”), or 2 to 6 carbon atoms (“C₂-C₆ alkynyl”), or 2to 4 carbon atoms (“C₂-C₄ alkynyl”). Representative examples include,but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or3-butynyl, and the like. Alkynyl groups are unsubstituted or substitutedby the same groups that are described herein as suitable for alkyl.

“Alkylene” as used herein refers to a divalent hydrocarbyl group havingthe specified number of carbon atoms which can link two other groupstogether. Sometimes it refers to a group —(CH₂)_(t)— where t is 1-8, andpreferably t is 1-4. Where specified, an alkylene can also besubstituted by other groups and may include one or more degrees ofunsaturation (i.e., an alkenylene or alkynlene moiety) or rings. Theopen valences of an alkylene need not be at opposite ends of the chain.Thus branched alkylene groups such as —CH(Me)-, —CH₂CH(Me)- and —C(Me)₂-are also included within the scope of the term ‘alkylenes’, as arecyclic groups such as cyclopropan-1,1-diyl and unsaturated groups suchas ethylene (—CH═CH—) or propylene (—CH₂—CH═CH—). Where an alkylenegroup is described as optionally substituted, the substituents includethose typically present on alkyl groups as described herein.

“Heteroalkylene” refers to an alkylene group as described above, whereinone or more non-contiguous carbon atoms of the alkylene chain arereplaced by —N(R)—, —O— or —S(O)_(x)—, where R is H or a suitablesubstituent group (e.g., R⁶) and x is 0-2. For example, the group—O—(CH₂)₁₋₄— is a ‘C₂-C₅’-heteroalkylene group, where one of the carbonatoms of the corresponding alkylene is replaced by O.

“Alkoxy” refers to a monovalent —O-alkyl group, wherein the alkylportion has the specified number of carbon atoms. Alkoxy groupstypically contain 1 to 8 carbon atoms (“C₁-C₈ alkoxy”), or 1 to 6 carbonatoms (“C₁-C₆ alkoxy”), or 1 to 4 carbon atoms (“C₁-C₄ alkoxy”). Forexample, C₁-C₄ alkoxy includes methoxy, ethoxy, isopropoxy,tert-butyloxy (i.e., —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —OC(CH₃)₃), and thelike. Alkoxy groups are unsubstituted or substituted on the alkylportion by the same groups that are described herein as suitable foralkyl. In particular, alkoxy groups may be optionally substituted by oneor more halo atoms, and in particular one or more fluoro atoms, up tothe total number of hydrogen atoms present on the alkyl portion. Suchgroups are referred to as “haloalkoxy” (or, where fluorinated, morespecifically as “fluoroalkoxy”) groups having the specified number ofcarbon atoms and substituted by one or more halo substituents, Typicallysuch groups contain from 1-6 carbon atoms, preferably 1-4 carbon atoms,and sometimes 1-2 carbon atoms, and 1, 2 or 3 halo atoms (i.e., “C₁-C₆haloalkoxy”, “C₁-C₄ haloalkoxy” or “C₁-C₂ haloalkoxy”). Morespecifically, fluorinated alkyl groups may be specifically referred toas fluoroalkoxy groups, e.g., C₁-C₆, C₁-C₄ or C₁-C₂ fluoroalkoxy groups,which are typically substituted by 1, 2 or 3 fluoro atoms. Thus, a C₁-C₄fluoroalkoxy includes trifluoromethyloxy (—OCF₃), difluoromethyloxy(—OCF₂H), fluoromethyloxy (—OCFH₂), difluoroethyloxy (—OCH₂CF₂H), andthe like.

Similarly, “thioalkoxy” refers to a monovalent —S-alkyl group, whereinthe alkyl portion has the specified number of carbon atoms, and isoptionally substituted on the alkyl portion by the same groups that aredescribed herein as suitable for alkyl. For example, a C₁-C₄ thioalkoxyincludes —SCH₃ and —SCH₂CH₃.

“Cycloalkyl” refers to a non-aromatic, saturated or partiallyunsaturated carbocyclic ring system containing the specified number ofcarbon atoms, which may be a monocyclic, spirocyclic, bridged or fusedbicyclic or polycyclic ring system that is connected to the basemolecule through a carbon atom of the cycloalkyl ring. Typically, thecycloalkyl groups of the invention contain 3 to 12 carbon atoms (“C₃-C₁₂cycloalkyl”), preferably 3 to 8 carbon atoms (“C₃-C₈ cycloalkyl”).Representative examples include, e.g., cyclopropane, cyclobutane,cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene,cycloheptane, cycloheptatriene, adamantane, and the like. Cycloalkylgroups are unsubstituted or substituted by the same groups that aredescribed herein as suitable for alkyl.

Illustrative examples of cycloalkyl rings include, but are not limitedto, the following:

“Cycloalkylalkyl” is used to describe a cycloalkyl ring, typically aC₃-C₈ cycloalkyl, which is connected to the base molecule through analkylene linker, typically a C₁-C₄ alkylene. Cycloalkylalkyl groups aresometimes described by the total number of carbon atoms in thecarbocyclic ring and linker, and typically contain from 4-12 carbonatoms (“C₄-C₁₂ cycloalkylalkyl”). Thus a cyclopropylmethyl group is aC₄-cycloalkylalkyl group and a cyclohexylethyl is a C₈-cycloalkylalkyl.Cycloalkylalkyl groups are unsubstituted or substituted on thecycloalkyl and/or alkylene portions by the same groups that aredescribed herein as suitable for alkyl groups. Sometimes cycloalkylalkylgroups are described herein, as -L- C₃-C₈-cycloalkyl, where thecycloalkyl group has the number of carbon atoms indicated and -L- refersto an alkylene linker. It will be understood that when -L- is a bond,the group is cycloalkyl.

The terms “heterocyclyl”, “heterocyclic” or “heteroalicyclic” are usedinterchangeably herein to refer to a non-aromatic, saturated orpartially unsaturated ring system containing the specified number ofring atoms, including at least one heteroatom selected from N, O and Sas a ring member, where ring S atoms are optionally substituted by oneor two oxo groups (i.e., S(O)_(x), where x is 0, 1 or 2) and where theheterocyclic ring is connected to the base molecule via a ring atom,which may be C or N. Heterocyclic rings include rings which arespirocyclic, bridged, or fused to one or more other heterocyclic orcarbocyclic rings, where such spirocyclic, bridged, or fused rings maythemselves be saturated, partially unsaturated or aromatic to the extentunsaturation or aromaticity makes chemical sense, provided the point ofattachment to the base molecule is an atom of the heterocyclic portionof the ring system. Preferably, heterocyclic rings contain 1 to 4heteroatoms selected from N, O, and S(O)_(q) as ring members, and morepreferably 1 to 2 ring heteroatoms, provided that such heterocyclicrings do not contain two contiguous oxygen atoms. Heterocyclyl groupsare unsubstituted or substituted by suitable substituent groups, forexample the same groups that are described herein as suitable for alkyl,aryl or heteroaryl. Such substituents may be present on the heterocyclicring attached to the base molecule, or on a spirocyclic, bridged orfused ring attached thereto. In addition, ring N atoms are optionallysubstituted by groups suitable for an amine, e.g., alkyl, acyl,carbamoyl, sulfonyl substituents, and the like.

Heterocycles typically include 3-12 membered heterocyclyl groups,preferably 3-10 membered heterocyclyl groups, and more preferably 5-6membered heterocyclyl groups, in accordance with the definition herein.

Illustrative examples of saturated heterocycles include, but are notlimited to:

Illustrative examples of partially unsaturated heterocycles include, butare not limited to:

Illustrative examples of bridged, fused and spiro heterocycles include,but are not limited to:

In frequent embodiments, heterocyclic groups contain 3-12 ring members,including both carbon and non-carbon heteroatoms, and preferably 4-7ring members. In certain preferred embodiments, substituent groupscomprising 3-12 membered heterocycles are selected from azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, morpholinyl and thiomorpholinyl rings, each ofwhich are optionally substituted as described for the particularsubstituent group, to the extent such substitution makes chemical sense.

It is understood that no more than two N, O or S atoms are ordinarilyconnected sequentially, except where an oxo group is attached to N or Sto form a nitro or sulfonyl group, or in the case of certainheteroaromatic rings, such as triazine, triazole, tetrazole, oxadiazole,thiadiazole, and the like.

The term “heterocyclylalkyl” may be used to describe a heterocyclicgroup of the specified size that is connected to the base moleculethrough an alkylene linker of the specified length. Typically, suchgroups contain an optionally substituted 3-12 membered heterocycleattached to the base molecule through a C₁-C₄ alkylene linker. Where soindicated, such groups are optionally substituted on the alkyleneportion by the same groups that are described herein as suitable foralkyl groups and on the heterocyclic portion by groups described assuitable for heterocyclic rings. Sometimes heterocyclylalkyl groups aredescribed herein as -L-heterocyclylalkyl, where the heterocyclylalkylgroup has the number of ring atoms indicated and -L- refers to analkylene linker. It will be understood that when -L- is a bond, thegroup is heterocyclyl.

“Aryl” or “aromatic” refer to an optionally substituted monocyclic orfused bicyclic or polycyclic ring system having the well-knowncharacteristics of aromaticity, wherein at least one ring contains acompletely conjugated pi-electron system. Typically, aryl groups contain6 to 20 carbon atoms (“C₆-C₂₀ aryl”) as ring members, preferably 6 to 14carbon atoms (“C₆-C₁₄ aryl”) or more preferably, 6 to 12 carbon atoms(“C₆-C₁₂ aryl”). Fused aryl groups may include an aryl ring (e.g., aphenyl ring) fused to another aryl or heteroaryl ring, or fused to asaturated or partially unsaturated carbocyclic or heterocyclic ring,provided the point of attachment to the base molecule on such fused ringsystems is an atom of the aromatic portion of the ring system. Examples,without limitation, of aryl groups include phenyl, biphenyl, naphthyl,anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl.The aryl group is unsubstituted or substituted as further describedherein.

Similarly, “heteroaryl” or “heteroaromatic” refer to monocyclic or fusedbicyclic or polycyclic ring systems having the well-knowncharacteristics of aromaticity that contain the specified number of ringatoms and include at least one heteroatom selected from N, O and S as aring member in an aromatic ring. The inclusion of a heteroatom permitsaromaticity in 5-membered rings as well as 6-membered rings. Typically,heteroaryl groups contain 5 to 20 ring atoms (“5-20 memberedheteroaryl”), preferably 5 to 14 ring atoms (“5-14 memberedheteroaryl”), and more preferably 5 to 12 ring atoms (“5-12 memberedheteroaryl”). Heteroaryl rings are attached to the base molecule via aring atom of the heteroaromatic ring, such that aromaticity ismaintained. Thus, 6-membered heteroaryl rings may be attached to thebase molecule via a ring C atom, while 5-membered heteroaryl rings maybe attached to the base molecule via a ring C or N atom. Heteroarylgroups may also be fused to another aryl or heteroaryl ring, or fused toa saturated or partially unsaturated carbocyclic or heterocyclic ring,provided the point of attachment to the base molecule on such fused ringsystems is an atom of the heteroaromatic portion of the ring system.Examples of unsubstituted heteroaryl groups often include, but are notlimited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole,oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran,benzothiophene, indole, benzimidazole, indazole, quinoline,isoquinoline, purine, triazine, naphthyridine and carbazole. In frequentpreferred embodiments, 5- or 6-membered heteroaryl groups are selectedfrom the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl,imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl,pyridinyl and pyrimidinyl, pyrazinyl or pyridazinyl rings. Theheteroaryl group is unsubstituted or substituted as further describedherein.

Aryl, heteroaryl and heterocyclyl moieties described herein asoptionally substituted may be substituted by one or more substituentgroups, which are selected independently unless otherwise indicated. Thetotal number of substituent groups may equal the total number ofhydrogen atoms on the aryl, heteroaryl or heterocyclyl moiety, to theextent such substitution makes chemical sense and aromaticity ismaintained in the case of aryl and heteroaryl rings. Optionallysubstituted aryl, heteroaryl or heterocyclyl groups typically containfrom 1 to 5 optional substituents, sometimes 1 to 4 optionalsubstituents, preferably 1 to 3 optional substituents, or morepreferably from 1-2 optional substituents.

Optional substituent groups suitable for aryl, heteroaryl andheterocyclyl rings include, but are not limited to: C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, 3-12 membered heterocyclyl,C₆-C₁₂ aryl and 5-12 membered heteroaryl; and halo, ═O, —CN, —C(O)R^(x),—CO₂R^(x), —C(O)NR^(x)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x),—SO₂NR^(x)R^(y), —NO₂, —NR^(x)R^(y), —NR^(x)C(O)R^(y),—NR^(x)C(O)NR^(x)R^(y), —NR^(x)C(O)OR^(x), —NR^(x)SO₂R^(y),—NR^(x)SO₂NR^(x)R^(y), —OR^(x), —OC(O)R^(x) and —OC(O)NR^(x)R^(y); whereeach R^(x) and R^(y) is independently H, C₁-C₈ alkyl, C₁-C₈ acyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, 3-12 membered heterocyclyl,C₆-C₁₂ aryl, or 5-12 membered heteroaryl, or R^(x) and R^(y) may betaken together with the N atom to which they are attached to form a 3-12membered heterocyclyl or 5-12 membered heteroaryl, each optionallycontaining 1, 2 or 3 additional heteroatoms selected from O, N andS(O)_(q) where q is 0-2; each R^(x) and R^(y) is optionally substitutedwith 1 to 3 substituents independently selected from the groupconsisting of halo, ═O, ═S, ═N—CN, ═N—OR′, ═NR′, —CN, —C(O)R′, —CO₂R,—C(O)NR′₂, —SR′, —SOR′, —SO₂R′, —SO₂NR′₂, —NO₂, —NR′₂, —NR′C(O)R′,—NR′C(O)NR′₂, —NR′C(O)OR′, —NR′SO₂R′, —NR′SO₂NR′₂, —OR′, —OC(O)R′ and—OC(O)NR′₂, wherein each R′ is independently H, C₁-C₈ alkyl, C₁-C₈ acyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, 3-12 memberedheterocyclyl, C₆-C₁₂ aryl, or 5-12 membered heteroaryl; and each saidC₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, 3-12membered heterocyclyl, C₆-C₁₂ aryl and 5-12 membered heteroaryl isoptionally substituted as further defined herein.

In typical embodiments, optional substitution on aryl, heteroaryl andheterocyclyl rings includes one or more substituents, and preferably 1to 3 substituents, independently selected from the group consisting ofhalo, C₁-C₈ alkyl, —OH, C₁-C₈ alkoxy, —CN, ═O, —C(O)R^(x), —COOR^(x),—OC(O)R^(x), —C(O)NR^(x)R^(y), —NR^(x)C(O)R^(y), —SR^(x), —SOR^(x),—SO₂R^(x), —SO₂NR^(x)R^(y), —NO₂, —NR^(x)R^(y), —NR^(x)C(O)R^(y),—NR^(x)C(O)NR^(x)R^(y), —NR^(x)C(O)OR^(y)—NR^(x)SO₂R^(y),—NR^(x)SO₂NR^(x)R^(y), —OC(O)R^(x), —OC(O)NR^(x)R^(y), C₃-C₈ cycloalkyl,3-12 membered heterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl,—O—(C₃-C₆ cycloalkyl), —O-(3-12 membered heterocyclyl), —O—(C₆-C₁₂ aryl)and —O-(5-12 membered heteroaryl); where each R^(x) and R^(y) isindependently H or C₁-C₄ alkyl, or R^(x) and R^(y) may be taken togetherwith the N to which they are attached form a 3-12 membered heterocyclylor 5-12 membered heteroaryl ring, each optionally containing 1, 2 or 3additional heteroatoms selected from O, N and S(O)_(q) where q is 0-2;and wherein each said C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₆ cycloalkyl, 3-12membered heterocyclyl, C₆-C₁₂ aryl, 5-12 membered heteroaryl, —O—(C₃-C₈cycloalkyl), —O-(3-12 membered heterocyclyl), —O—(C₆-C₁₂ aryl) and—O-(5-12 membered heteroaryl) that is described as an optionalsubstituent or is part of R^(x) or R^(y) is optionally substituted by 1to 3 substituents independently selected from the group consisting ofhalo, —OH, ═O, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₄ alkoxy-C₁-C₆ alkyl, —CN, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂ and N-pyrrolidinyl.

Examples of monocyclic heteroaryl groups include, but are not limitedto:

Illustrative examples of fused ring heteroaryl groups include, but arenot limited to:

An “arylalkyl” group refers to an aryl group as described herein whichis linked to the base molecule through an alkylene or similar linker.Arylalkyl groups are described by the total number of carbon atoms inthe ring and linker. Thus a benzyl group is a C₇-arylalkyl group and aphenylethyl is a C₈-arylalkyl. Typically, arylalkyl groups contain 7-16carbon atoms (“C₇-C₁₆ arylalkyl”), wherein the aryl portion contains6-12 carbon atoms and the alkylene portion contains 1-4 carbon atoms.Such groups may also be represented as —C₁-C₄ alkylene-C₆-C₁₂ aryl.

“Heteroarylalkyl” refers to a heteroaryl group as described above thatis attached to the base molecule through an alkylene linker, and differsfrom “arylalkyl” in that at least one ring atom of the aromatic moietyis a heteroatom selected from N, O and S. Heteroarylalkyl groups aresometimes described herein according to the total number of non-hydrogenatoms (i.e., C, N, S and O atoms) in the ring and linker combined,excluding substituent groups. Thus, for example, pyridinylmethyl may bereferred to as a “C₇”-heteroarylalkyl. Typically, unsubstitutedheteroarylalkyl groups contain 6-20 non-hydrogen atoms (including C, N,S and O atoms), wherein the heteroaryl portion typically contains 5-12atoms and the alkylene portion typically contains 1-4 carbon atoms. Suchgroups may also be represented as —C₁-C₄ alkylene-5-12 memberedheteroaryl. Sometimes heteroarylalkyl groups are described herein as -L-heteroarylalkyl, where the heteroarylalkyl group has the number of ringatoms indicated and -L- refers to an alkylene linker. It will beunderstood that when -L- is a bond, the group is heteroaryl.

Similarly, “arylalkoxy” and “heteroarylalkoxy” refer to aryl andheteroaryl groups, attached to the base molecule through aheteroalkylene linker (i.e., —O-alkylene-), wherein the groups aredescribed according to the total number of non-hydrogen atoms (i.e., C,N, S and O atoms) in the ring and linker combined. Thus, —O—CH₂-phenyland —O—CH₂-pyridinyl groups would be referred to as C₈-arylalkoxy andC₈-heteroarylalkoxy groups, respectively.

Where an arylalkyl, arylalkoxy, heteroarylalkyl or heteroarylalkoxygroup is described as optionally substituted, the substituents may be oneither the divalent linker portion or on the aryl or heteroaryl portionof the group. The substituents optionally present on the alkylene orheteroalkylene portion are the same as those described above for alkylor alkoxy groups generally, while the substituents optionally present onthe aryl or heteroaryl portion are the same as those described above foraryl or heteroaryl groups generally.

“Hydroxy” refers to an —OH group.

“Acyloxy” refers to a monovalent group —OC(O)alkyl, wherein the alkylportion has the specified number of carbon atoms (typically C₁-C₈,preferably C₁-C₆ or C₁-C₄) that are optionally substituted by groupssuitable for alkyl. Thus, C₁-C₄ acyloxy includes an —OC(O)C₁-C₄ alkylsubstituent, e.g., —OC(O)CH₃.

“Acyl” refers to a monovalent group —C(O)alkyl, wherein the alkylportion has the specified number of carbon atoms (typically C₁-C₈,preferably C₁-C₆ or C₁-C₄) and may be optionally substituted by groupssuitable for alkyl, e.g., by F, OH or alkoxy. Thus, optionallysubstituted —C(O)C₁-C₄ alkyl includes unsubstituted acyl groups, such as—C(O)CH₃ (i.e., acetyl) and —C(O)CH₂CH₃ (i.e., propionyl), as well assubstituted acyl groups such as —C(O)CF₃ (trifluoroacetyl), —C(O)CH₂OH(hydroxyacetyl), —C(O)CH₂OCH₃ (methoxyacetyl), —C(O)CF₂H(difluoroacetyl), and the like.

“Acylamino” refers to a monovalent group, —NHC(O)alkyl or —NRC(O)alkyl,wherein the alkyl portion has the specified number of carbon atoms(typically C₁-C₈, preferably C₁-C₆ or C₁-C₄) and is optionallysubstituted by groups suitable for alkyl. Thus, C₁-C₄ acylamino includesan —NHC(O)C₁-C₄ alkyl substituent, e.g., —NHC(O)CH₃.

“Aryloxy” or “heteroaryloxy” refer to optionally substituted —O-aryl or—O-heteroaryl, in each case where aryl and heteroaryl are as furtherdefined herein.

“Arylamino” or “heteroarylamino” refer to optionally substituted—NH-aryl, —NR-aryl, —NH-heteroaryl or —NR-heteroaryl, in each case wherearyl and heteroaryl are as further defined herein and R represents asubstituent suitable for an amine, e.g., an alkyl, acyl, carbamoyl orsulfonyl group, or the like.

“Cyano” refers to a —C≡N group.

“Unsubstituted amino” refers to a group —NH₂. Where the amino isdescribed as substituted or optionally substituted, the term includesgroups of the form —NR^(x)R^(y), where each or R^(x) and R^(y) isindependently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,acyl, thioacyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl orheteroarylalkyl, in each case having the specified number of atoms andoptionally substituted as described herein. For example, “alkylamino”refers to a group —NR^(x)R^(y), wherein one of R^(x) and R^(y) is analkyl moiety and the other is H, and “dialkylamino” refers to—NR^(x)R^(y) wherein both of R^(x) and R^(y) are alkyl moieties, wherethe alkyl moieties having the specified number of carbon atoms (e.g.,—NH—C₁-C₄ alkyl or —N(C₁-C₄ alkyl)₂). Typically, alkyl substituents onamines contain 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, ormore preferably 1 to 4 carbon atoms. The term also includes formswherein R^(x) and R^(y) are taken together with the N atom to which theyare attached to form a 3-12 membered heterocyclyl or 5-12 memberedheteroaryl ring, each of which may itself be optionally substituted asdescribed herein for heterocyclyl or heteroaryl rings, and which maycontain 1 to 3 additional heteroatoms selected from N, O and S(O)_(x)where x is 0-2 as ring members, provided that such rings do not containtwo contiguous oxygen atoms.

“Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br,I). Preferably, halo refers to fluoro or chloro (F or Cl).

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and the description includesinstances where the event or circumstance occurs and instances in whichit does not.

The terms “optionally substituted” and “substituted or unsubstituted”are used interchangeably to indicate that the particular group beingdescribed may have no non-hydrogen substituents (i.e., unsubstituted),or the group may have one or more non-hydrogen substituents (i.e.,substituted). If not otherwise specified, the total number ofsubstituents that may be present is equal to the number of H atomspresent on the unsubstituted form of the group being described. Where anoptional substituent is attached via a double bond, such as an oxo (═O)substituent, the group occupies two available valences, so the totalnumber of other substituents that are included is reduced by two. In thecase where optional substituents are selected independently from a listof alternatives, the selected groups are the same or different.Throughout the disclosure, it will be understood that the number andnature of optional substituent groups will be limited to the extent thatsuch substitutions make chemical sense.

In one aspect, the invention provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A) or C₃-C₈cycloalkyl substituted by R^(5B), where said 3-10 membered heterocyclyland C₃-C₈ cycloalkyl are optionally further substituted by one or moreR⁶;

each R² is independently F, OH, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₄alkoxy or C₁-C₄ fluoroalkoxy;

R^(2A) and R^(2B) are independently H, F, OH, C₁-C₄ alkyl, C₁-C₄fluoroalkyl, C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy;

-   -   where each said C₁-C₄ alkyl and C₁-C₄ fluoroalkyl in R², R^(2A)        and R^(2B) is independently optionally substituted by OH, C₁-C₄        alkoxy or C₁-C₄ fluoroalkoxy;

R³ is H, F, Cl, NH₂, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄alkyl and C₁-C₄ fluoroalkyl are optionally substituted by OH, CN, C₁-C₄alkoxy, C₁-C₄ fluoroalkoxy, CONH₂ and COOH;

R⁴ is H, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl;

R^(5A) is SO₂R⁷, SO₂NR⁸R⁹, NHSO₂R⁷ or NHSO₂NR⁸R⁹;

R^(5B) is NHSO₂R⁷ or NHSO₂NR⁸R⁹;

each R⁶ is independently F, OH, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₄alkoxy or C₁-C₄ fluoroalkoxy;

R⁷ is C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, -L-(C₃-C₈ cycloalkyl), -L-(5-6membered heterocyclyl) or -L-(5-6 membered heteroaryl);

R⁸ and R⁹ are independently H, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, -L-(C₃-C₈cycloalkyl), -L-(5-6 membered heterocyclyl) or -L-(5-6 memberedheteroaryl); or

R⁸ and R⁹ may be taken together with the nitrogen atom to which they areattached to form a 5-6 membered heterocyclyl;

-   -   where each said C₁-C₄ alkyl and C₁-C₄ fluoroalkyl in R⁷, R⁸ and        R⁹ is optionally substituted by OH, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy or SO₂Me, and each said C₃-C₈ cycloalkyl, 5-6        membered heterocyclyl and 5-6 membered heteroaryl in R⁷, R⁸ and        R⁹ is optionally substituted by C₁-C₄ alkyl, OH, C₁-C₄ alkoxy or        C₁-C₄ fluoroalkoxy;

L is a bond or C₁-C₄ alkylene, where said C₁-C₄ alkylene is optionallysubstituted by C₁-C₄ alkyl, OH, C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2; and

r is 0, 1 or 2.

In some embodiments, the compound of Formula (I) has the absolutestereochemistry as shown in Formula (I-A), (I-B) or (I-C):

or a pharmaceutically acceptable salt thereof, where R¹, R², R^(2A),R^(2B), R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸, R⁹, p, q and r are definedas for Formula (I).

Each of the aspects and embodiments described herein with respect toFormula (I) is also applicable to compounds of Formula (I-A), (I-B) or(I-C).

In compounds of Formula (I), R¹ is 3-10 membered heterocyclylsubstituted by R^(5A) or C₃-C₈ cycloalkyl substituted by R^(5B), wheresaid 3-10 membered heterocyclyl and C₃-C₈ cycloalkyl are optionallyfurther substituted by one or more R⁶.

In some embodiments of Formula (I), R¹ is 3-10 membered heterocyclylsubstituted by R^(5A) and optionally further substituted by one or moreR⁶. In some such embodiments, R¹ is 5-6 membered heterocyclylsubstituted by R^(5A) and optionally further substituted by one or moreR⁶. In some such embodiments, R¹ is 5-6 membered heterocyclylsubstituted by R^(5A). In particular embodiments, R¹ is a 5-6 memberednitrogen-containing heterocyclyl substituted by R^(5A). In some suchembodiments, R¹ is a piperidinyl or pyrrolidinyl ring. In specificembodiments, R¹ is a piperidin-4-yl, piperidin-3-yl or pyrrolidin-3-yl.In frequent embodiments, R¹ is a 5-6 membered nitrogen-containingheterocyclyl which is N-substituted by R^(5A). In frequent embodiments,R^(j) is a piperidin-4-yl for which N¹ of the piperidinyl ring issubstituted by R^(5A). In other embodiments, R¹ is a piperidin-3-yl forwhich N¹ of the piperidinyl ring is substituted by R^(5A). In furtherembodiments, R¹ is a pyrrolidin-3-yl for which N¹ of the pyrrolidinylring is substituted by R^(5A).

In each of the foregoing embodiments, R¹ is optionally furthersubstituted by one or more R⁶. In some embodiments, R¹ is optionallyfurther substituted by one, two or three R⁶. In further embodiments, R¹is optionally further substituted by one or two R⁶. In some embodiments,R¹ is a 3-10 membered nitrogen-containing heterocyclyl substituted byR^(5A) and further substituted by one, two or three R⁶, where each R⁶ isindependently F, OH, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy orC₁-C₄ fluoroalkoxy, as further described herein. In some embodiments, R¹is a 3-10 membered nitrogen-containing heterocyclyl substituted byR^(5A) and further substituted by one or two R⁶, where each R⁶ isindependently F or CH₃.

In particular embodiments, R¹ is a 5-6 membered nitrogen-containingheterocyclyl that is N-substituted by R^(5A), which is selected from thegroup consisting of:

where the * represents the point of attachment to the 2-aminosubstituent.

In particular embodiments, R¹ is

In some such embodiments, R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹.

In compounds of Formula (I), R^(5A) is SO₂R⁷, SO₂NR⁸R⁹, NHSO₂R⁷ orNHSO₂NR⁸R⁹, where R⁷, R⁸ and R⁹ are as defined for Formula (I) andfurther described herein. In some embodiments of Formula (I), R¹ is 3-10membered heterocyclyl and R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹. In otherembodiments, R¹ is 3-10 membered heterocyclyl and R^(5A) is NHSO₂R⁷ orNHSO₂NR⁸R⁹.

In some embodiments of Formula (I), R¹ is 3-10 membered heterocyclyl andR^(5A) is SO₂R⁷ or SO₂NR⁸R⁹. In some such embodiments, R¹ is piperidinylor pyrrolidinyl and R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹. In particularembodiments, R¹ is a piperidin-4-yl, piperidin-3-yl or pyrrolidin-3-yland R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹. In frequent embodiments, R¹ is apiperidin-4-yl for which N¹ of the piperidinyl ring is substituted byR^(5A), where R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹. In other embodiments, R¹ is apiperidin-3-yl for which N¹ of the piperidinyl ring is substituted byR^(5A), where R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹. In other embodiments, R¹ is apyrrolidin-3-yl for which N of the pyrrolidinyl ring is substituted byR^(5A), where R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹. In each of the foregoingembodiments, R¹ is optionally further substituted by one or more R⁶.

In some embodiments of Formula (I), R¹ is 5-6 membered heterocyclyl andR^(5A) is SO₂R⁷. In other embodiments of Formula (I), R¹ is 5-6 memberedN-containing heterocyclyl and R^(5A) is SO₂R⁷. In frequent embodiments,R¹ is 5-6 membered N-containing heterocyclyl substituted at N by R^(5A),where R^(5A) is SO₂R⁷. In some such embodiments, R⁷ is CH₃. In specificembodiments, R¹ is a piperidin-4-yl substituted at N¹ by R^(5A), whereR^(5A) is SO₂R⁷ and R⁷ is CH₃.

In still other embodiments of Formula (I), R¹ is 5-6 memberedheterocyclyl and R^(5A) is SO₂NR⁸R⁹. In some such embodiments, R⁸ and R⁹are independently H or CH₃. In particular embodiments, R¹ is apiperidin-4-yl substituted at N¹ by R^(5A), where R^(5A) is SO₂NR⁸R⁹ andR⁸ and R⁹ are independently H or CH₃.

In other embodiments of Formula (I), R¹ is C₃-C₈ cycloalkyl, where saidC₃-C₈ cycloalkyl is substituted by R^(5B) and optionally furthersubstituted by one or more R⁶. In some such embodiments, R¹ iscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In each of theforegoing, R¹ is substituted by R^(5B) and optionally furthersubstituted by one or more R⁶. In other embodiments of Formula (I),R^(5B) is NHSO₂R⁷ or NHSO₂NR⁸R⁹.

In compounds of Formula (I), R⁷ is C₁-C₄ alkyl, C₁-C₄ fluoroalkyl,-L-(C₃-C₈ cycloalkyl), -L-(5-6 membered heterocyclyl) or -L-(5-6membered heteroaryl), where R⁷ is optionally substituted as describedfor Formula (I) above.

In compounds of Formula (I), L is a bond or C₁-C₄ alkylene, where saidC₁-C₄ alkylene is optionally substituted by OH, C₁-C₄ alkoxy or C₁-C₄fluoroalkoxy. In some embodiments, R⁷ is C₁-C₄ alkyl, optionallysubstituted by OH, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy or SO₂Me. Inparticular embodiments, R⁷ is C₁-C₄ alkyl. In some such embodiments, R⁷is CH₃. In other such embodiments, R⁷ is CH₂CH₃. In further embodiments,R⁷ is C₁-C₄ alkyl, optionally substituted by OH, OCH₃ or SO₂Me. In someembodiments, R⁷ is C₁-C₄ fluoroalkyl. In some such embodiments, R⁷ isCH₂F, CHF₂, CH₂CF₂H, CF₃ or CH₂CF₃.

In further embodiments, R⁷ is -L-(C₃-C₈ cycloalkyl), where said C₃-C₈cycloalkyl is optionally substituted by C₁-C₄ alkyl, OH, C₁-C₄ alkoxy orC₁-C₄ fluoroalkoxy. In some such embodiments, L is a bond and R⁷ iscyclopropyl, cyclobutyl, cyclopentyl. In other such embodiments, L ismethylene (i.e. —CH₂—) and R⁷ is cyclopropylmethyl, cyclobutylmethyl orcycloheptylmethyl.

In still other embodiments, R⁷ is -L-(5-6 membered heterocyclyl) or-L-(5-6 membered heteroaryl), where said 5-6 membered heterocyclyl and5-6 membered heteroaryl are optionally substituted by C₁-C₄ alkyl, OH,C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy. In some such embodiments, L is abond, methylene or ethylene moiety (i.e., bond, —CH₂— or —CH₂CH₂—) andR⁷ is an optionally substituted 5-6 membered heteroaryl selected fromthe group consisting of pyrazolyl, imidazolyl, thiazolyl orthiadiazolyl. In some such embodiments, L is a bond. In other suchembodiments, L is a bond, methylene or ethylene and R⁷ is an optionallysubstituted 5-6 membered heterocyclyl. In a specific embodiment, L is abond and R⁷ is dioxidotetrahydrothiophenyl.

In some embodiments R^(5A) is SO₂R⁷, where R⁷ is selected from each ofthe foregoing embodiments described for R⁷. In some embodiments, R^(5A)is SO₂R⁷ and R⁷ is C₁-C₄ alkyl optionally substituted by OH, C₁-C₄alkoxy, C₁-C₄ fluoroalkoxy or SO₂Me. In particular embodiments, R^(5A)is SO₂R⁷ and R⁷ is C₁-C₄ alkyl. In specific embodiments of each of theforegoing embodiments of R⁷, R¹ is piperidinyl or pyrrolidinyl, inparticular piperidin-4-yl, piperidin-3-yl or pyrrolidin-3-yl, and R^(5A)is SO₂R⁷.

In compounds of Formula (I), R⁸ and R⁹ are independently H, C₁-C₄ alkyl,C₁-C₄ fluoroalkyl, -L-(C₃-C₈ cycloalkyl), -L-(5-6 membered heterocyclyl)or -L-(5-6 membered heteroaryl); or R⁸ and R⁹ may be taken together withthe nitrogen atom to which they are attached to form a 5-6 memberedheterocyclyl, where R⁸ and R⁹ are optionally substituted as describedfor Formula (I) above or further described herein.

In some embodiments of Formula (I), R⁸ and R⁹ are independently H orC₁-C₄ alkyl. In some such embodiments, R⁸ and R⁹ are independently H orCH₃. In some embodiments, both R⁸ and R⁹ are H. In other embodiments, R⁸is H and R⁹ is CH₃. In still other embodiments, both R⁸ and R⁹ are CH₃.In further embodiments, one of R⁸ and R⁹ is H and the other is C₁-C₄alkyl or C₁-C₄ fluoroalkyl, each optionally substituted as describedherein. In some such embodiments, R⁸ is H and R⁹ is C₁-C₄ alkyl or C₁-C₄fluoroalkyl, optionally substituted by OH or C₁-C₄ alkoxy, In stillother embodiments, one of R⁸ and R⁹ is H and the other is -L-(C₃-C₈cycloalkyl), -L-(5-6 membered heterocyclyl) or -L-(5-6 memberedheteroaryl), each optionally substituted as described herein. In somesuch embodiments, R⁸ is H and R⁹ is -L-(5-6 membered heterocyclyl),where L is a bond, methylene or ethylene. In specific embodiments, R⁸ isH and R⁹ is tetrahydrofuranyl or tetrahydropyranyl, wherein L is a bond,or tetrahydrofuranylmethyl or tetrahydropyranylmethyl, wherein L ismethylene. In some such embodiments, L is a bond.

In some embodiments R^(5A) is SO₂NR⁸R⁹ where R⁸ and R⁹ are selected fromeach of the foregoing embodiments described for R⁸ and R⁹. In particularembodiments of each of the foregoing embodiments of R⁸ and R⁹, R¹ ispiperidinyl or pyrrolidinyl, in particular piperidin-4-yl,piperidin-3-yl or pyrrolidin-3-yl, and R^(5A) is SO₂NR⁸R⁹.

In some embodiments of Formula (I), Rand R⁹ are taken together with thenitrogen atom to which they are attached to form a 5-6 memberedheterocyclyl, where said 5-6 membered heterocyclyl is optionallysubstituted by C₁-C₄ alkyl, OH, C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy. Insome such embodiments, R⁸ and R⁹ are taken together with the nitrogenatom to which they are attached to form an optionally substitutedpiperidinyl ring. In addition to the N to which R⁸ and R⁹ are attached,said 5-6 membered heterocyclyl may optionally include an additionalheteroatom selected from N, O and S as a ring member, where ring S atomsare optionally substituted by one or two oxo groups (i.e., S(O)_(x),where x is 0, 1 or 2). In some such embodiments, R⁸ and R⁹ are takentogether with the nitrogen atom to which they are attached to form anoptionally substituted pyrrolidinyl ring. In further embodiments, R⁸ andR⁹ are taken together with the nitrogen atom to which they are attachedto form an optionally substituted morpholinyl or a piperazinyl ring.

In compounds of Formula (I), each R⁶ is independently F, OH, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy. Infrequent embodiments, R⁶ is absent. In some such embodiments, each R⁶ isindependently F or C₁-C₄ alkyl. In some embodiments, R¹ is a 5-6membered nitrogen-containing heterocyclyl substituted by R^(5A) andfurther substituted by one, two or three R⁶, where each R⁶ isindependently F or C₁-C₄ alkyl. In some such embodiments, R¹ is a 5-6membered nitrogen-containing heterocyclyl substituted by R^(5A) andfurther substituted by one R⁶, where R⁶ is F. In other embodiments, R¹is a 5-6 membered nitrogen-containing heterocyclyl substituted by R^(5A)and further substituted by one or two R⁶, where each R⁶ is CH₃.

In compounds of Formula (I), p is 0, 1, 2, 3 or 4, where p is an integerthat represents the number of optional substituent groups, R².

In compounds of Formula (I), each R² is independently F, OH, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy, where eachsaid C₁-C₄ alkyl and C₁-C₄ fluoroalkyl is optionally substituted by OH,C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy. In frequent embodiments, p is 0 andR² is absent. In other embodiments, p is 1 or 2. In some embodiments, pis 1 or 2, and each R² is independently F, OH or C₁-C₄ alkyl. In someembodiments, p is 1 or 2, and each R² is independently F, OH or CH₃. Insome such embodiments p is 1 and R² is F or CH₃.

In compounds of Formula (I), R^(2A) and R^(2B) are independently H, F,OH, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy,where each said C₁-C₄ alkyl and C₁-C₄ fluoroalkyl is optionallysubstituted by OH, C₁-C₄ alkoxy or C₁-C₄ fluoroalkoxy.

In some embodiments, R^(2A) and R^(2B) are independently H, OH or C₁-C₄alkyl. In particular embodiments, R^(2A) and R^(2B) are independently H,OH or CH₃.

In preferred embodiments of Formula (I), at least one of R^(2A) andR^(2B) is not H. In particular embodiments, R^(2A) and R^(2B) areindependently H, F, OH, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy orC₁-C₄ fluoroalkoxy, provided at least one of R^(2A) and R^(2B) is not H.In specific embodiments, R^(2A) and R^(2B) are independently H, OH orCH₃, provided at least one of R^(2A) and R^(2B) is not H.

In some embodiments of Formula (I), one of R^(2A) and R^(2B) is OH andthe other is CH₃. In other embodiments, one of R^(2A) and R^(2B) is OHand the other is H. In other embodiments, one of R^(2A) and R^(2B) is Hand the other is CH₃.

In specific embodiments of Formula (I), (I-A), (I-B) or (I-C), R^(2A) isOH and R^(2B) is CH₃. In other such embodiments, R^(2A) is OH and R^(2B)is H. In further embodiments, R^(2A) is H and R^(2B) is CH₃.

In further embodiments of Formula (I), (I-A), (I-B) or (I-C), R^(2B) isOH and R^(2A) is CH₃. In other such embodiments, R^(2B) is OH and R^(2A)is H. In further embodiments, R^(2B) is H and R^(2A) is CH₃.

In compounds of Formula (I), R³ is H, F, Cl, NH₂, C₁-C₄ alkyl or C₁-C₄fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄ fluoroalkyl are optionallysubstituted by OH, CN, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, CONH₂ and COOH.In some embodiments of Formula (I), R³ is H, F, Cl, C₁-C₄ alkyl or C₁-C₄fluoroalkyl, where said C₁-C₄ alkyl or C₁-C₄ fluoroalkyl are optionallysubstituted by OH. In other embodiments, R³ is H, F, Cl, CH₃, CH₂CH₂OH,CF₂H or CH₂CF₂H. In other embodiments of Formula (I), R³ is F, Cl, C₁-C₄alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄ fluoroalkylare optionally substituted by OH, CN, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy,CONH₂ and COOH. In some such embodiments, R³ is F, Cl, CH₃, CH₂CH₂OH,CF₂H or CH₂CF₂H. In some embodiments of Formula (I), R³ is H.

In other embodiments of Formula (I), R³ is F or Cl. In some suchembodiments, R³ is F. In other such embodiments, R³ is Cl.

In other embodiments of Formula (I), R³ is NH₂. In some embodiments ofFormula (I), R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄alkyl and C₁-C₄ fluoroalkyl are optionally substituted by OH, CN, C₁-C₄alkoxy, C₁-C₄ fluoroalkoxy, CONH₂ and COOH. In some such embodiments, R³is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH.

In some embodiments of Formula (I), R³ is C₁-C₄ alkyl, optionallysubstituted by OH, CN, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, CONH₂ and COOH.In some such embodiments, R³ is C₁-C₂ alkyl, optionally substituted byOH, CN, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, CONH₂ and COOH. In someembodiments of Formula (I), R³ is C₁-C₂ alkyl, optionally substituted byOH. In some embodiments, R³ is CH₃ or CH₂CH₃. In some embodiments, R³ isCH₂OH, CH₂CH₂OH, CH₂OCH₃ or CH₂CH₂OCH₃. In other embodiments, R³ isCH₂CN, CH₂CONH₂ or CH₂COOH.

In other embodiments of Formula (I), R³ is C₁-C₄ fluoroalkyl, optionallysubstituted by OH, CN, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, CONH₂ and COOH.In some such embodiments, R³ is C₁-C₂ fluoroalkyl, optionallysubstituted by OH, CN, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, CONH₂ and COOH.In some embodiments of Formula (I), R³ is C₁-C₂ alkyl, optionallysubstituted by OH.

In some embodiments, R³ is C₁-C₄ fluoroalkyl. In other embodiments, R³is C₁-C₂ fluoroalkyl. In specific embodiments, R³ is CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂ or CH₂CH₂F. In certain embodiments, R³ is CHF₂ orCH₂CHF₂. In some such embodiments, R³ is CHF₂. In other suchembodiments, R³ is CH₂CHF₂.

In compounds of Formula (I), R⁴ is H, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.In frequent embodiments, R⁴ is H. In some embodiments, R⁴ is C₁-C₂alkyl, such as CH₃.

In particular embodiments, R⁴ is H and R³ is C₁-C₄ fluoroalkyl. In somesuch embodiments, R⁴ is H and R³ is C₁-C₂ fluoroalkyl. In specificembodiments, R⁴ is H and R³ is CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂ orCH₂CH₂F. In certain preferred embodiments, R⁴ is H and R³ is CHF₂ orCH₂CHF₂.

In some embodiments of each of the foregoing embodiments described forR³, R⁴ is H. In other embodiments of each of the foregoing embodimentsdescribed for R³, R⁴ is C₁-C₂ alkyl or C₁-C₂ fluoroalkyl. In particularembodiments of each of the foregoing embodiments described for R³, R⁴ isCH₃, CH₂CH₃, CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂ or CH₂CH₂F.

In compounds of Formula (I), q is 0, 1 or 2; and r is 0, 1 or 2. In someembodiments, q is 1 and r is 0. In other embodiments, q is 0 and r is 1.In other embodiments, q is 1 and r is 1. In still other embodiments, qis 2 and r is 0. In further embodiments, q is 2 and r is 1. In someembodiments, the sum of q and r is 0, 1, 2 or 3. In some suchembodiments, the ring comprising q and r is a cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl ring, substituted by R^(2A) and R^(2B) andoptionally substituted by R². In preferred embodiments, the ringcomprising q and r is a cyclopentyl or cyclohexyl ring. In someembodiments, the sum of q and r is less than or equal to 3. In otherembodiments, the sum of q and r is less than or equal to 2. In stillother embodiments, the sum of q and r is 1 or 2.

In certain preferred embodiments, the invention provides a compound ofFormula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A);

p is 0 and R² is absent;

q is 1 and r is 0; or

q is 1 and r is 1;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl;

R³ is H, F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A); or

R¹ is 3-10 membered heterocyclyl substituted by R^(5A), where said 3-10membered heterocyclyl is optionally further substituted by one or twoR⁶;

p is 0 and R² is absent; or

p is 1 or 2, and each R² is independently F, OH or CH₃;

q is 1 and r is 0; or

q is 0 and r is 1; or

q is 1 and r is 1;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent; or

each R⁶ is independently F or CH₃;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In further preferred embodiments, the invention provides a compound ofFormula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptablesalt thereof, having three or more of the following features:

R¹ is 5-6 membered heterocyclyl substituted by R^(5A); or

R¹ is 5-6 membered heterocyclyl substituted by R^(5A), where said 5-6membered heterocyclyl is optionally further substituted by one or twoR⁶;

p is 0 and R² is absent;

q is 1 and r is 0; or

q is 1 and r is 1;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent; or

each R⁶ is independently F or CH₃;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

p is 0 and R² is absent;

q is 1 and r is 0;

R^(2A) and R^(2B) are independently H, OH or CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In still other preferred embodiments, the invention provides a compoundof Formula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptablesalt thereof, having three or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

p is 0 and R² is absent;

q is 1 and r is 0; or

q is 1 and r is 1; R^(2A) and R^(2B) are independently H, OH or CH₃,provided at least one of R^(2A) and R^(2B) is not H;

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides a compound ofFormula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

p is 0 and R² is absent;

q is 1 and r is 0;

one of R^(2A) and R^(2B) is OH and the other is CH₃; or

one of R^(2A) and R^(2B) is OH and the other is H; or

one of R^(2A) and R^(2B) is H and the other is CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In other preferred embodiments, the invention provides a compound ofFormula (I), (I-A), (I-B) and (I-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is piperidin-4-yl, substituted on N¹ by R^(5A);

p is 0 and R² is absent;

q is 1 and r is 0;

R^(2A) is OH and R^(2B) is H; or

R^(2A) is OH and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is CH₃;

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R;

R⁶ is absent; and

R⁷ is CH₃.

In specific embodiments, the invention provides compounds of Formula(I-B), or a pharmaceutically acceptable salt thereof, having two or moreof the following features:

R¹ is piperidin-4-yl, substituted on N¹ by R^(5A);

p is 0 and R² is absent;

q is 1 and r is 0;

R^(2A) is H or OH and R^(2B) is H or CH₃; or

R^(2A) is OH and R^(2B) is H; or

R^(2A) is OH and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is H;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷, where R⁷ is CH₃; or

R^(5A) is SO₂NR⁸R⁹, where R⁸ is H or CH₃ and R⁹ is CH₃; and

R⁶ is absent.

In another aspect, the invention provides a compound of Formula (II),(II-A), (II-B) or (II-C):

or a pharmaceutically acceptable salt thereof, where R¹, R², R^(2A),R^(2B), R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸, R⁹ and p are defined as forFormula (I).

The embodiments described herein for Formula (I) with respect to R¹, R²,R^(2A), R^(2B), R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸, R⁹ and p are alsoapplicable to compounds of Formulae (II), (II-A), (II-B) and (II-C) tothe extent they are not inconsistent.

In certain preferred embodiments, the invention provides a compound ofFormula (II), (II-A), (II-B) and (II-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A);

p is 0 and R² is absent;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl;

R³ is H, F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (II), (II-A), (II-B) and (II-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A); or

R¹ is 3-10 membered heterocyclyl substituted by R^(5A), where said 3-10membered heterocyclyl is optionally further substituted by one or twoR⁶;

p is 0 and R² is absent; or

p is 1 or 2, and each R² is independently F, OH or CH₃;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁶R⁹;

R⁶ is absent; or

each R⁶ is independently F or CH₃;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (II), (II-A), (II-B) and (II-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is 5-6 membered heterocyclyl substituted by R^(5A); or

R¹ is 5-6 membered heterocyclyl substituted by R^(5A), where said 5-6membered heterocyclyl is optionally further substituted by one or moreR⁶;

p is 0 and R² is absent; R^(2A) and R^(2B) are independently H, OH orC₁-C₄ alkyl, provided at least one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent; or

each R⁶ is independently F or CH₃;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In still other preferred embodiments, the invention provides a compoundof Formula (II), (II-A), (II-B) and (II-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

p is 0 and R² is absent;

R^(2A) and R^(2B) are independently H, OH or CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In other preferred embodiments, the invention provides a compound ofFormula (II), (II-A), (II-B) and (II-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

p is 0 and R² is absent;

R^(2A) and R^(2B) are independently H, OH or CH₃, provided at least oneof R^(2A) and R^(2B) is not H;

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides a compound ofFormula (II), (II-A), (II-B) and (II-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

p is 0 and R² is absent;

one of R^(2A) and R^(2B) is OH and the other is CH₃; or

one of R^(2A) and R^(2B) is OH and the other is H; or

one of R^(2A) and R^(2B) is H and the other is CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides compounds ofFormula (II-B), or a pharmaceutically acceptable salt thereof, havingtwo or more of the following features:

R¹ is piperidin-4-yl, substituted on N¹ by R^(5A);

p is 0 and R² is absent;

R^(2A) is OH and R^(2B) is H; or

R^(2A) is OH and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is CH₃; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷;

R⁶ is absent; and

R⁷ is CH₃.

In further preferred embodiments, the invention provides compounds ofFormula (II-B), or a pharmaceutically acceptable salt thereof, havingtwo or more of the following features:

R¹ is piperidin-4-yl, substituted on N¹ by R^(5A);

p is 0 and R² is absent;

R^(2A) is H or OH and R^(2B) is H or CH₃; or

R^(2A) is OH and R^(2B) is H; or

R^(2A) is OH and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is H;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷, where R⁷ is CH₃; or

R^(5A) is SO₂NR⁸R⁹, where R⁸ is H or CH₃ and R⁹ is CH₃; and

R⁶ is absent.

In another aspect, the invention provides a compound of Formula (III),(III-A), (III-B) or (III-C):

or a pharmaceutically acceptable salt thereof, where R¹, R², R^(2A),R^(2B), R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸, R⁹ and p are defined as forFormula (I).

The embodiments described herein for Formula (I) with respect to R¹, R²,R^(2A), R^(2B), R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸, R⁹ and p are alsoapplicable to compounds of Formulae (III), (III-A), (III-B) and (III-C)to the extent they are not inconsistent.

In certain preferred embodiments, the invention provides a compound ofFormula (III), (III-A), (III-B) and (III-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A);

p is 0 and R² is absent;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl;

R³ is H, F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other embodiments, the invention provides a compound of Formula(III), (III-A), (III-B) and (III-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A); or

R¹ is 3-10 membered heterocyclyl substituted by R^(5A), where said 3-10membered heterocyclyl is optionally further substituted by one or twoR⁶;

p is 0 and R² is absent; or

p is 1 or 2, and each R² is independently F, OH or CH₃;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent; or

each R⁶ is independently F or CH₃;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (III), (III-A), (III-B) and (III-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is 5-6 membered heterocyclyl substituted by R^(5A); or

R¹ is 5-6 membered heterocyclyl substituted by R^(5A), where said 5-6membered heterocyclyl is optionally further substituted by one or moreR⁶;

p is 0 and R² is absent;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent; or

each R⁶ is independently F or CH₃;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (III), (II-A), (III-B) and (III-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

p is 0 and R² is absent;

R^(2A) and R^(2B) are independently H, OH or CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In other preferred embodiments, the invention provides a compound ofFormula (III), (III-A), (III-B) and (III-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

p is 0 and R² is absent;

R^(2A) and R^(2B) are independently H, OH or CH₃, provided at least oneof R^(2A) and R^(2B) is not H;

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides a compound ofFormula (III), (III-A), (III-B) and (III-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

p is 0 and R² is absent;

one of R^(2A) and R^(2B) is OH and the other is CH₃; or

one of R^(2A) and R^(2B) is OH and the other is H; or

one of R^(2A) and R^(2B) is H and the other is CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In another aspect, the invention provides a compound of Formula (IV),(IV-A), (IV-B) or (IV-C):

or a pharmaceutically acceptable salt thereof, where R¹, R^(2A), R^(2B),R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸ and R⁹ are defined as for Formula(I).

The embodiments described herein for Formula (I) with respect to R¹,R^(2A), R^(2B), R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸ and R⁹ are alsoapplicable to compounds of Formulae (IV), (IV-A), (IV-B) and (IV-C) tothe extent they are not inconsistent.

In specific embodiments, the compounds of Formula (IV), (IV-A), (IV-B)and (IV-C) have the structure:

or a pharmaceutically acceptable salt thereof, where R¹, R³, R⁴, R^(5A),R^(5B), R⁶, R⁷, R⁸ and R⁹ are defined as for Formula (I).

In certain preferred embodiments, the invention provides a compound ofFormula (IV), (IV-A), (IV-B) and (IV-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A).

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl;

R³ is H, F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In another preferred embodiments, the invention provides a compound ofFormula (IV), (IV-A), (IV-B) and (IV-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A);

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In another preferred embodiments, the invention provides a compound ofFormula (IV), (IV-A), (IV-B) and (IV-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is 5-6 membered heterocyclyl substituted by R^(5A);

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (IV), (IV-A), (IV-B) and (IV-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

R^(2A) and R^(2B) are independently H, OH or CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In another preferred embodiments, the invention provides a compound ofFormula (IV), (IV-A), (IV-B) and (IV-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

R^(2A) and R^(2B) are independently H, OH or CH₃, provided at least oneof R^(2A) and R^(2B) is not H;

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides a compound ofFormula (IV), (IV-A), (IV-B) and (IV-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

one of R^(2A) and R^(2B) is OH and the other is CH₃; or

one of R^(2A) and R^(2B) is OH and the other is H; or

one of R^(2A) and R^(2B) is H and the other is CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides compounds ofFormula (IV-B), or a pharmaceutically acceptable salt thereof, havingtwo or more of the following features:

R¹ is piperidin-4-yl, substituted on N¹ by R^(5A);

R^(2A) is OH and R^(2B) is H; or

R^(2A) is OH and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is CH₃; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷;

R⁶ is absent; and

R⁷ is CH₃.

In further preferred embodiments, the invention provides compounds ofFormula (IV-B), or a pharmaceutically acceptable salt thereof, havingtwo or more of the following features:

R¹ is piperidin-4-yl, substituted on N¹ by R^(5A);

R^(2A) is H or OH and R^(2B) is H or CH₃; or

R^(2A) is OH and R^(2B) is H; or

R^(2A) is OH and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is H;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷, where R⁷ is CH₃; or

R^(5A) is SO₂NR⁸R⁹, where R⁸ is H or CH₃ and R⁹ is CH₃; and

R⁶ is absent.

In other preferred embodiments, the invention provides compounds ofFormula (iv), (iv-a), (iv-b) or (iv-c), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is piperidin-4-yl, substituted on N¹ by R^(5A);

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷, where R⁷ is CH₃; or

R^(5A) is SO₂NR⁸R⁹, where R⁸ is H or CH₃ and R⁹ is CH₃; and

R⁶ is absent.

In other preferred embodiments, the invention provides compounds ofFormula (iv-f) or (iv-g), or a pharmaceutically acceptable salt thereof,wherein:

R¹ is piperidin-4-yl, substituted on N¹ by R^(5A);

R^(5A) is SO₂R⁷, where R⁷ is CH₃; or

R^(5A) is SO₂NR⁸R⁹, where R⁸ is H or CH₃ and R⁹ is CH₃; and

R⁶ is absent.

In another aspect, the invention provides a compound of Formula (V),(V-A), (V-B) or (V-C):

or a pharmaceutically acceptable salt thereof, where R¹. R^(2A), R^(2B),R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸ and R⁹ are defined as for Formula(I).

The embodiments described herein for Formula (I) with respect to R¹,R^(2A), R^(2B), R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸ and R⁹ are alsoapplicable to compounds of Formulae (V), (V-A), (V-B) and (V-C) to theextent they are not inconsistent.

In specific embodiments, the compounds of Formula (V), (V-A), (V-B) and(V-C) have the structure:

or a pharmaceutically acceptable salt thereof, where R¹, R³, R⁴, R^(5A),R^(5B), R⁶, R⁷, R⁸ and R⁹ are defined as for Formula (I).

In certain preferred embodiments, the invention provides a compound ofFormula (V), (V-A), (V-B) and (V-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A);

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl;

R³ is H, F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In another preferred embodiments, the invention provides a compound ofFormula (V), (V-A), (V-B) and (V-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is 3-10 membered heterocyclyl substituted by R^(5A); or

R¹ is 3-10 membered heterocyclyl substituted by R^(5A), where said 3-10membered heterocyclyl is optionally further substituted by one or twoR⁶;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent; or each R⁶ is independently F or CH₃;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In another preferred embodiments, the invention provides a compound ofFormula (V), (V-A), (V-B) and (V-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is 5-6 membered heterocyclyl substituted by R^(5A); or

R¹ is 5-6 membered heterocyclyl substituted by R^(5A), where said 5-6membered heterocyclyl is optionally further substituted by one or twoR⁶;

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent; or

each R⁶ is independently F or CH₃;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (V), (V-A), (V-B) and (V-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

R^(2A) and R^(2B) are independently H, OH or CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In another preferred embodiments, the invention provides a compound ofFormula (V), (V-A), (V-B) and (V-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

R^(2A) and R^(2B) are independently H, OH or CH₃, provided at least oneof R^(2A) and R^(2B) is not H;

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides a compound ofFormula (V), (V-A), (V-B) and (V-C), or a pharmaceutically acceptablesalt thereof, having two or more of the following features:

R¹ is piperidinyl, preferably piperidin-4-yl, substituted on N¹ byR^(5A);

one of R^(2A) and R^(2B) is OH and the other is CH₃; or

one of R^(2A) and R^(2B) is OH and the other is H; or

one of R^(2A) and R^(2B) is H and the other is CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁶ is absent;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In another aspect, the invention provides a compound of Formula (VI),(VI-A), (VI-B) or (VI-C):

or a pharmaceutically acceptable salt thereof, where R^(2A), R^(2B), R³,R⁴, R^(5A), R⁷, R⁸ and R⁹ are defined as for Formula (I).

The embodiments described herein for Formula (I) with respect to R^(2A),R^(2B), R³, R⁴, R^(5A), R^(5B), R⁶, R⁷, R⁸ and R⁹ are also applicable tocompounds of Formulae (VI), (VI-A), (VI-B) and (VI-C) to the extent theyare not inconsistent.

In certain preferred embodiments, the invention provides a compound ofFormula (VI), (VI-A), (VI-B) and (VI-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl;

R³ is H, F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (VI), (VI-A), (VI-B) and (VI-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁷ is C₁-C₄ alkyl; or

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl; or

R⁸ and R⁹ are independently H or CH₃.

In other preferred embodiments, the invention provides a compound ofFormula (VI), (VI-A), (VI-B) and (VI-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R^(2A) and R^(2B) are independently H, OH or CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides a compound ofFormula (VI), (VI-A), (VI-B) and (VI-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

one of R^(2A) and R^(2B) is OH and the other is CH₃; or

one of R^(2A) and R^(2B) is OH and the other is H; or

one of R^(2A) and R^(2B) is H and the other is CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides compounds ofFormula (VI-B), or a pharmaceutically acceptable salt thereof, havingtwo or more of the following features:

R^(2A) is H or OH and R^(2B) is H or CH₃; or

R^(2A) is OH and R^(2B) is H; or

R^(2A) is OH and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is H;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H; and

R^(5A) is SO₂R⁷, where R⁷ is CH₃; or

R^(5A) is SO₂NR⁸R⁹, where R⁸ is H or CH₃ and R⁹ is CH₃.

In further preferred embodiments, the invention provides compounds ofFormula (VI-B), or a pharmaceutically acceptable salt thereof, havingtwo or more of the following features:

one of R^(2A) and R^(2B) is OH and the other is CH₃; or

one of R^(2A) and R^(2B) is OH and the other is H; or

one of R^(2A) and R^(2B) is H and the other is CH₃; or

R^(2A) is OH and R^(2B) is H; or

R^(2A) is OH and R^(2B) is CH₃; or

R^(2A) is H and R^(2B) is CH₃;

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H; and

R^(5A) is SO₂R⁷, and

R⁷ is CH₃.

In another aspect, the invention provides a compound of Formula (VII),(VII-A), (VII-B) or (VII-C):

or a pharmaceutically acceptable salt thereof, where R^(2A), R^(2B), R³,R⁴, R^(5A), R⁷, R⁸ and R⁹ are defined as for Formula (I).

The embodiments described herein for Formula (I) with respect to R^(2A),R^(2B), R³, R⁴, R^(5A), R⁷, R⁸ and R⁹ are also applicable to compoundsof Formulae (VII), (VII-A), (VII-B) and (VII-C) to the extent they arenot inconsistent.

In certain preferred embodiments, the invention provides a compound ofFormula (VII), (VII-A), (VII-B) and (VII-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl;

R³ is H, F, Cl, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyland C₁-C₄ fluoroalkyl are optionally substituted by OH;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁷ is C₁-C₄ alkyl; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl.

In other preferred embodiments, the invention provides a compound ofFormula (VII), (VII-A), (VII-B) and (VII-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R^(2A) and R^(2B) are independently H, OH or C₁-C₄ alkyl, provided atleast one of R^(2A) and R^(2B) is not H;

R³ is C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where said C₁-C₄ alkyl and C₁-C₄fluoroalkyl are optionally substituted by OH; or

R³ is C₁-C₄ fluoroalkyl; or

R³ is C₁-C₂ fluoroalkyl; or

R³ is CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁷ is C₁-C₄ alkyl; or

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or C₁-C₄ alkyl; or

R⁸ and R⁹ are independently H or CH₃.

In other preferred embodiments, the invention provides a compound ofFormula (VII), (VII-A), (VII-B) and (VII-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

R^(2A) and R^(2B) are independently H, OH or CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In further preferred embodiments, the invention provides a compound ofFormula (VII), (VII-A), (VII-B) and (VII-C), or a pharmaceuticallyacceptable salt thereof, having two or more of the following features:

one of R^(2A) and R^(2B) is OH and the other is CH₃; or

one of R^(2A) and R^(2B) is OH and the other is H; or

one of R^(2A) and R^(2B) is H and the other is CH₃;

R³ is H, F, Cl, CH₃, CH₂CH₂OH, CF₂H or CH₂CF₂H;

R⁴ is H;

R^(5A) is SO₂R⁷ or SO₂NR⁸R⁹;

R⁷ is CH₃; and

R⁸ and R⁹ are independently H or CH₃.

In another aspect, the invention provides a compound selected from thegroup consisting of:

-   8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   8-[(1R,3R)-3-hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   4-({6-(2-hydroxyethyl)-8-[(1R,2S)-2-methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-methylpiperidine-1-sulfonamide;-   (+)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   (−)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   (+)-6-(2,2-difluoroethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   (−)-6-(2,2-difluoroethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-chloro-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;    and-   6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of:

-   (−)-6-(difluoromethyl)-8-[(1R*,3R*)-3-hydroxycyclopentyl]-2-{[1-(methylsulfonyl)-piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   (+)-6-(difluoromethyl)-8-[(1R*,3R*)-3-hydroxycyclopentyl]-2-{[1-(methylsulfonyl)-piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   (8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetonitrile;-   8-cyclopentyl-6-(2-hydroxyethyl)-2-{[1-(propan-2-ylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-amino-2-{[1-(but-3-yn-1-ylsulfonyl)piperidin-4-yl]amino}-8-cyclopentylpyrido[2,3-d]pyrimidin-7(8H)-one;-   8-cyclopentyl-6-ethenyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-6-(prop-2-en-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;    and-   6-(2,2-difluoroethyl)-8-[(1R,3R)-3-hydroxycyclohexyl]-2-{[1-(methylsulfonyl)-piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of the compounds exemplified in Table 1, comprisingExamples 11-132 and 141-226, inclusive, or a pharmaceutically acceptablesalt thereof. In another aspect, the invention provides a compoundselected from the group consisting of the compounds exemplified inExamples 1 to 226 herein, or a pharmaceutically acceptable salt thereof.

The compounds of the invention were optimized for selectivity againstCDK2 versus CDK1. Preferably, compounds showed at least 20-foldselectivity for CDK2 versus CDK1, and more preferably, compounds showedat least 30-fold selectivity for CDK2 versus CDK1. Compounds of theinvention were also optimized to enhance physicochemical properties,such as increased aqueous solubility and decreased clearance in humanliver microsome (HLM) models.

A “pharmaceutical composition” refers to a mixture of one or more of thecompounds described herein, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof as an active ingredient, and atleast one pharmaceutically acceptable carrier or excipient. In someembodiments, the pharmaceutical composition comprises two or morepharmaceutically acceptable carriers and/or excipients. In otherembodiments, the pharmaceutical composition further comprises at leastone additional anticancer therapeutic agent.

In another aspect the invention provides a pharmaceutical compositioncomprising a compound of one of the formulae described herein, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient. In some embodiments, the pharmaceuticalcomposition comprises two or more pharmaceutically acceptable carriersand/or excipients.

In some embodiments, the pharmaceutical composition further comprises atleast one additional anti-cancer therapeutic agent or a palliativeagent. In some such embodiments, the at least one additional agent is ananti-cancer therapeutic agent as described below. In some suchembodiments, the combination provides an additive, greater thanadditive, or synergistic anti-cancer effect.

In one aspect, the invention provides a method for the treatment ofabnormal cell growth in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of the invention, or a pharmaceutically acceptable saltthereof.

In another aspect, the invention provides a method for the treatment ofabnormal cell growth in a subject in need thereof, comprisingadministering to the subject an amount of a compound of the invention,or a pharmaceutically acceptable salt thereof, in combination with anamount of an additional therapeutic agent (e.g., an anticancertherapeutic agent), which amounts are together effective in treatingsaid abnormal cell growth.

In frequent embodiments of the methods provided herein, the abnormalcell growth is cancer. Compounds of the invention may be administered assingle agents, or may be administered in combination with otheranti-cancer therapeutic agents, in particular standard of care agentsappropriate for the particular cancer.

In some embodiments, the methods provided result in one or more of thefollowing effects: (1) inhibiting cancer cell proliferation; (2)inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancercells; (4) inhibiting cancer cell metastasis; or (5) inhibitingangiogenesis.

In another aspect, the invention provides a method for the treatment ofa disorder mediated by CDK2, CDK4 and/or CDK6, in a subject, such ascertain cancers, comprising administering to the subject a compound ofthe invention, or a pharmaceutically acceptable salt thereof, in anamount that is effective for treating said disorder.

Unless indicated otherwise, all references herein to the inventivecompounds include references to salts, solvates, hydrates and complexesthereof, and to solvates, hydrates and complexes of salts thereof,including polymorphs, stereoisomers, and isotopically labelled versionsthereof.

Compounds of the invention may exist in the form of pharmaceuticallyacceptable salts such as, e.g., acid addition salts and base additionsalts of the compounds of one of the formulae provided herein. As usedherein, the term “pharmaceutically acceptable salt” refers to thosesalts which retain the biological effectiveness and properties of theparent compound. The phrase “pharmaceutically acceptable salt(s)”, asused herein, unless otherwise indicated, includes salts of acidic orbasic groups which may be present in the compounds of the formulaedisclosed herein.

For example, the compounds of the invention that are basic in nature arecapable of forming a wide variety of salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate the compound of the present invention from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention can be prepared by treating thebase compound with a substantially equivalent amount of the selectedmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon evaporation of thesolvent, the desired solid salt is obtained. The desired acid salt canalso be precipitated from a solution of the free base in an organicsolvent by adding an appropriate mineral or organic acid to thesolution.

The acids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds of those that form non-toxic acidaddition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Examples of salts include, but are not limited to, acetate, acrylate,benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate,bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate,calcium edetate, camsylate, carbonate, chloride, caproate, caprylate,clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate,edetate, edislyate, estolate, esylate, ethylsuccinate, formate,fumarate, gluceptate, gluconate, glutamate, glycollate,glycollylarsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide,isobutyrate, isothionate, lactate, lactobionate, laurate, malate,maleate, malonate, mandelate, mesylate, metaphosphate,methane-sulfonate, methylsulfate, monohydrogenphosphate, mucate,napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate,oleate, oxalate, pamoate (embonate), palmitate, pantothenate,phenylacetates, phenylbutyrate, phenylpropionate, phthalate,phospate/diphosphate, polygalacturonate, propanesulfonate, propionate,propiolate, pyrophosphate, pyrosulfate, salicylate, stearate,subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate,tartrate, teoclate, tosylate, triethiodode and valerate salts.

Illustrative examples of suitable salts include organic salts derivedfrom amino acids, such as glycine and arginine, ammonia, primary,secondary, and tertiary amines and cyclic amines, such as piperidine,morpholine and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminumand lithium.

The compounds of the invention that include a basic moiety, such as anamino group, may form pharmaceutically acceptable salts with variousamino acids, in addition to the acids mentioned above.

Those compounds of the invention that are acidic in nature are capableof forming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline-earth metalsalts and particularly, the sodium and potassium salts. These salts areall prepared by conventional techniques. The chemical bases which areused as reagents to prepare the pharmaceutically acceptable base saltsof this invention are those which form non-toxic base salts with theacidic compounds herein. These salts may be prepared by any suitablemethod, for example, treatment of the free acid with an inorganic ororganic base, such as an amine (primary, secondary or tertiary), analkali metal hydroxide or alkaline earth metal hydroxide, or the like.These salts can also be prepared by treating the corresponding acidiccompounds with an aqueous solution containing the desiredpharmacologically acceptable cations, and then evaporating the resultingsolution to dryness, preferably under reduced pressure. Alternatively,they may also be prepared by mixing lower alkanolic solutions of theacidic compounds and the desired alkali metal alkoxide together, andthen evaporating the resulting solution to dryness in the same manner asbefore. In either case, stoichiometric quantities of reagents arepreferably employed in order to ensure completeness of reaction andmaximum yields of the desired final product.

The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of the compounds of the inventionthat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto, those derived from such pharmacologically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).Methods for making pharmaceutically acceptable salts of compounds of theinvention are known to one of skill in the art.

Salts of the present invention can be prepared according to methodsknown to those of skill in the art. A pharmaceutically acceptable saltof the inventive compounds can be readily prepared by mixing togethersolutions of the compound and the desired acid or base, as appropriate.The salt may precipitate from solution and be collected by filtration ormay be recovered by evaporation of the solvent. The degree of ionizationin the salt may vary from completely ionized to almost non-ionized.

It will be understood by those of skill in the art that the compounds ofthe invention in free base form having a basic functionality may beconverted to the acid addition salts by treating with a stoichiometricexcess of the appropriate acid. The acid addition salts of the compoundsof the invention may be reconverted to the corresponding free base bytreating with a stoichiometric excess of a suitable base, such aspotassium carbonate or sodium hydroxide, typically in the presence ofaqueous solvent, and at a temperature of between about 0° C. and 100° C.The free base form may be isolated by conventional means, such asextraction with an organic solvent. In addition, acid addition salts ofthe compounds of the invention may be interchanged by taking advantageof differential solubilities of the salts, volatilities or acidities ofthe acids, or by treating with the appropriately loaded ion exchangeresin. For example, the interchange may be affected by the reaction of asalt of the compounds of the invention with a slight stoichiometricexcess of an acid of a lower pK than the acid component of the startingsalt. This conversion is typically carried out at a temperature betweenabout 0° C. and the boiling point of the solvent being used as themedium for the procedure. Similar exchanges are possible with baseaddition salts, typically via the intermediacy of the free base form.

The compounds of the invention may exist in both unsolvated and solvatedforms. When the solvent or water is tightly bound, the complex will havea well-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when the solvent is water. Pharmaceuticallyacceptable solvates in accordance with the invention include hydratesand solvates wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Also included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionized, partially ionized, or non-ionized. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975), the disclosure of which is incorporated herein by reference inits entirety.

The invention also relates to prodrugs of the compounds of the formulaeprovided herein. Thus, certain derivatives of compounds of the inventionwhich may have little or no pharmacological activity themselves can,when administered to a patient, be converted into the inventivecompounds, for example, by hydrolytic cleavage. Such derivatives arereferred to as ‘prodrugs’. Further information on the use of prodrugsmay be found in ‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series (T Higuchi and W Stella) and ‘Bioreversible Carriers inDrug Design’, Pergamon Press, 1987 (ed. E B Roche, AmericanPharmaceutical Association), the disclosures of which are incorporatedherein by reference in their entireties.

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the inventivecompounds with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in “Design of Prodrugs” by HBundgaard (Elsevier, 1985), the disclosure of which is incorporatedherein by reference in its entirety.

Some non-limiting examples of prodrugs in accordance with the inventioninclude:

(i) where the compound contains a carboxylic acid functionality (—COOH),an ester thereof, for example, replacement of the hydrogen with(C₁-C₈)alkyl;

(ii) where the compound contains an alcohol functionality (—OH), anether thereof, for example, replacement of the hydrogen with(C₁-C₆)alkanoyloxymethyl, or with a phosphate ether group; and

(iii) where the compound contains a primary or secondary aminofunctionality (—NH₂ or —NHR where R≠H), an amide thereof, for example,replacement of one or both hydrogens with a suitably metabolicallylabile group, such as an amide, carbamate, urea, phosphonate, sulfonate,etc.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Finally, certain inventive compounds may themselves act as prodrugs ofother of the inventive compounds.

Also included within the scope of the invention are metabolites ofcompounds of the formulae described herein, i.e., compounds formed invivo upon administration of the drug.

The compounds of the formulae provided herein may have asymmetric carbonatoms. The carbon-carbon bonds of the compounds of the invention may bedepicted herein using a solid line (

), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g. specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that only the stereoisomer shown ismeant to be included. It is possible that compounds of the invention maycontain more than one asymmetric carbon atom. In those compounds, theuse of a solid line to depict bonds to asymmetric carbon atoms is meantto indicate that all possible stereoisomers are meant to be included andthe attached stereocenter. For example, unless stated otherwise, it isintended that the compounds of the invention can exist as enantiomersand diastereomers or as racemates and mixtures thereof. The use of asolid line to depict bonds to one or more asymmetric carbon atoms in acompound of the invention and the use of a solid or dotted wedge todepict bonds to other asymmetric carbon atoms in the same compound ismeant to indicate that a mixture of diastereomers is present.

Compounds of the invention that have chiral centers may exist asstereoisomers, such as racemates, enantiomers, or diastereomers.

Stereoisomers of the compounds of the formulae herein can include cisand trans isomers, optical isomers such as (R) and (S) enantiomers,diastereomers, geometric isomers, rotational isomers, atropisomers,conformational isomers, and tautomers of the compounds of the invention,including compounds exhibiting more than one type of isomerism, andmixtures thereof (such as racemates and diastereomeric pairs).

Also included are acid addition or base addition salts wherein thecounterion is optically active, for example, d-lactate or I-lysine, orracemic, for example, dl-tartrate or dl-arginine.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The compounds of the invention may exhibit the phenomena of tautomerismand structural isomerism. For example, the compounds may exist inseveral tautomeric forms, including the enol and imine form, and theketo and enamine form and geometric isomers and mixtures thereof. Allsuch tautomeric forms are included within the scope of compounds of theinvention. Tautomers exist as mixtures of a tautomeric set in solution.In solid form, usually one tautomer predominates. Even though onetautomer may be described, the present invention includes all tautomersof the compounds of the formulae provided.

In addition, some of the compounds of the invention may formatropisomers (e.g., substituted biaryls). Atropisomers areconformational stereoisomers which occur when rotation about a singlebond in the molecule is prevented, or greatly slowed, as a result ofsteric interactions with other parts of the molecule and thesubstituents at both ends of the single bond are unsymmetrical. Theinterconversion of atropisomers is slow enough to allow separation andisolation under predetermined conditions. The energy barrier to thermalracemization may be determined by the steric hindrance to free rotationof one or more bonds forming a chiral axis.

Where a compound of the invention contains an alkenyl or alkenylenegroup, geometric cis/trans (or Z/E) isomers are possible. Cis/transisomers may be separated by conventional techniques well known to thoseskilled in the art, for example, chromatography and fractionalcrystallization.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC) or superfluid critical chromatography (SFC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound contains an acidic or basic moiety, an acidor base such as tartaric acid or 1-phenylethylamine. The resultingdiastereomeric mixture may be separated by chromatography and/orfractional crystallization and one or both of the diastereoisomersconverted to the corresponding pure enantiomer(s) by means well known toone skilled in the art.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50%isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine,typically 0.1% diethylamine. Concentration of the eluate affords theenriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art, see, for example, “Stereochemistry ofOrganic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosureof which is incorporated herein by reference in its entirety.

The enantiomeric purity of compounds described herein may be describedin terms of enantiomeric excess (ee), which indicates the degree towhich a sample contains one enantiomer in greater amounts than theother. A racemic mixture has an ee of 0%, while a single completely pureenantiomer has an ee of 100%. Similarly, diastereomeric purity may bedescribed in terms of diasteriomeric excess (de).

The present invention also includes isotopically-labeled compounds,which are identical to those recited in one of the formulae provided,but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber usually found in nature.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Examples of isotopes that may be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as, but not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl. Certainisotopically-labeled compounds of the invention, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Tritiated,i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferredfor their ease of preparation and detectability. Further, substitutionwith heavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically-labeledcompounds of the invention may generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting an isotopically-labeled reagent fora non-isotopically-labeled reagent.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products, or mixtures thereof.They may be obtained, for example, as solid plugs, powders, or films bymethods such as precipitation, crystallization, freeze drying, spraydrying, or evaporative drying. Microwave or radio frequency drying maybe used for this purpose.

Therapeutic Methods and Uses

The invention further provides therapeutic methods and uses comprisingadministering the compounds of the invention, or pharmaceuticallyacceptable salts thereof, alone or in combination with other therapeuticagents or palliative agents.

In one aspect, the invention provides a method for the treatment ofabnormal cell growth in a subject comprising administering to thesubject a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof. In frequentembodiments, the abnormal cell growth is cancer.

In another aspect, the invention provides a method for the treatment ofcancer in a subject comprising administering to the subject an amount ofa compound of the invention, or a pharmaceutically acceptable saltthereof, in combination with an amount of an additional anticancertherapeutic agent, which amounts are together effective in treating saidcancer.

Compounds of the invention include compounds of any of the formulaedescribed herein, or a pharmaceutically acceptable salt thereof.

In still another aspect, the invention provides a method of inhibitingcancer cell proliferation in a subject, comprising administering to thesubject a compound of the invention, or a pharmaceutically acceptablesalt thereof, in an amount effective to inhibit cell proliferation.

In another aspect, the invention provides a method of inhibiting cancercell invasiveness in a subject, comprising administering to the subjecta compound of the invention, or a pharmaceutically acceptable saltthereof, in an amount effective to inhibit cell invasiveness.

In another aspect, the invention provides a method of inducing apoptosisin cancer cells in a subject, comprising administering to the subject acompound of the invention, or a pharmaceutically acceptable saltthereof, in an amount effective to induce apoptosis.

In frequent embodiments of the methods provided herein, the abnormalcell growth is cancer characterized by amplification or overexpressionof CCNE1 and/or CCNE2. In some embodiments of the methods providedherein, the subject is identified as having a cancer characterized byamplification or overexpression of CCNE1 and/or CCNE2.

In frequent embodiments of the methods provided herein, the abnormalcell growth is cancer, wherein the cancer is selected from the groupconsisting of breast cancer, ovarian cancer, bladder cancer, uterinecancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamouscell carcinoma or adenocarcinoma), esophageal cancer, head and neckcancer, colorectal cancer, kidney cancer (including RCC), liver cancer(including HCC), pancreatic cancer, stomach (i.e., gastric) cancer andthyroid cancer. In further embodiments of the methods provided herein,the cancer is selected from the group consisting of breast cancer,ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lungcancer, esophageal cancer, liver cancer, pancreatic cancer and stomachcancer. In some such embodiments, the cancer is characterized byamplification or overexpression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is selected from the group consisting ofbreast cancer and ovarian cancer. In some such embodiments, the canceris breast cancer or ovarian cancer characterized by amplification oroverexpression of CCNE1 and/or CCNE2.

In some such embodiments, the cancer is (a) breast cancer or ovariancancer; (b) characterized by amplification or overexpression of cyclinE1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b).

In some embodiments, the cancer is ovarian cancer. In some suchembodiments, the ovarian cancer is characterized by amplification oroverexpression of CCNE1 and/or CCNE2.

In other embodiments, the cancer is breast cancer, including, e.g.,ER-positive/HR-positive breast cancer, HER2-negative breast cancer;ER-positive/HR-positive breast cancer, HER2-positive breast cancer;triple negative breast cancer (TNBC); or inflammatory breast cancer. Insome embodiments, the breast cancer is endocrine resistant breastcancer, trastuzumab resistant breast cancer, or breast cancerdemonstrating primary or acquired resistance to CDK4/CDK6 inhibition. Insome embodiments, the breast cancer is advanced or metastatic breastcancer. In some embodiments of each of the foregoing, the breast canceris characterized by amplification or overexpression of CCNE1 and/orCCNE2.

In some embodiments, the compound of the invention is administered asfirst line therapy. In other embodiments, the compound of the inventionis administered as second (or later) line therapy. In some embodiments,the compound of the invention is administered as second (or later) linetherapy following treatment with an endocrine therapeutic agent and/or aCDK4/CDK6 inhibitor. In some embodiments, the compound of the inventionis administered as second (or later) line therapy following treatmentwith an endocrine therapeutic agent. In some embodiments, the compoundof the invention is administered as second (or later) line therapyfollowing treatment with a CDK4/CDK6 inhibitor. In some embodiments, thecompound of the invention is administered as second (or later) linetherapy following treatment with one or more chemotherapy regimens,e.g., including taxanes or platinum agents. In some embodiments, thecompound of the invention is administered as second (or later) linetherapy following treatment with HER2 targeted agents, e.g.,trastuzumab. The term “therapeutically effective amount” as used hereinrefers to that amount of a compound being administered which willrelieve to some extent one or more of the symptoms of the disorder beingtreated. In reference to the treatment of cancer, a therapeuticallyeffective amount refers to that amount which has the effect of (1)reducing the size of the tumor, (2) inhibiting (that is, slowing to someextent, preferably stopping) tumor metastasis, (3) inhibiting to someextent (that is, slowing to some extent, preferably stopping) tumorgrowth or tumor invasiveness, and/or (4) relieving to some extent (or,preferably, eliminating) one or more signs or symptoms associated withthe cancer.

As used herein, “subject” refers to a human or animal subject. Incertain preferred embodiments, the subject is a human.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. The term “treating” alsoincludes adjuvant and neo-adjuvant treatment of a subject.

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). Abnormal cell growth maybe benign (not cancerous), or malignant (cancerous).

Abnormal cell growth includes the abnormal growth of: (1) tumor cells(tumors) that show increased expression of CDK2; (2) tumors thatproliferate by aberrant CDK2 activation; (3) tumors characterized byamplification or overexpression of CCNE1 and/or CCNE2; and (4) tumorsthat are resistant to endocrine therapy, HER2 antagonists or CDK4/6inhibition.

The term “additional anticancer therapeutic agent” as used herein meansany one or more therapeutic agent, other than a compound of theinvention, that is or can be used in the treatment of cancer, such asagents derived from the following classes: mitotic inhibitors,alkylating agents, antimetabolites, antitumor antibiotics, topoisomeraseI and II inhibitors, plant alkaloids, hormonal agents and antagonists,growth factor inhibitors, radiation, inhibitors of protein tyrosinekinases and/or serine/threonine kinases, cell cycle inhibitors,biological response modifiers, enzyme inhibitors, antisenseoligonucleotides or oligonucleotide derivatives, cytotoxics, andimmuno-oncology agents.

As used herein “cancer” refers to any malignant and/or invasive growthor tumor caused by abnormal cell growth. Cancer includes solid tumorsnamed for the type of cells that form them, cancer of blood, bonemarrow, or the lymphatic system. Examples of solid tumors includesarcomas and carcinomas. Cancers of the blood include, but are notlimited to, leukemia, lymphoma and myeloma. Cancer also includes primarycancer that originates at a specific site in the body, a metastaticcancer that has spread from the place in which it started to other partsof the body, a recurrence from the original primary cancer afterremission, and a second primary cancer that is a new primary cancer in aperson with a history of previous cancer of a different type from thelatter one.

In some embodiments of the methods provided herein, the cancer isselected from the group consisting of breast cancer, ovarian cancer,bladder cancer, uterine cancer, prostate cancer, lung cancer, esophagealcancer, liver cancer, pancreatic cancer and stomach cancer. In some suchembodiments, the cancer is characterized by amplification oroverexpression of CCNE1 and/or CCNE2.

Dosage Forms and Regimens

Administration of the compounds of the invention may be effected by anymethod that enables delivery of the compounds to the site of action.These methods include oral routes, intraduodenal routes, parenteralinjection (including intravenous, subcutaneous, intramuscular,intravascular or infusion), topical, and rectal administration.

Dosage regimens may be adjusted to provide the optimum desired response.For example, a single bolus may be administered, several divided dosesmay be administered over time or the dose may be proportionally reducedor increased as indicated by the exigencies of the therapeuticsituation. It is especially advantageous to formulate parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form, as used herein, refers tophysically discrete units suited as unitary dosages for the mammaliansubjects to be treated, each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on (a) the unique characteristics of the chemotherapeuticagent and the particular therapeutic or prophylactic effect to beachieved, and (b) the limitations inherent in the art of compoundingsuch an active compound for the treatment of sensitivity in individuals.

Thus, the skilled artisan would appreciate, based upon the disclosureprovided herein, that the dose and dosing regimen is adjusted inaccordance with methods well-known in the therapeutic arts. That is, themaximum tolerable dose can be readily established, and the effectiveamount providing a detectable therapeutic benefit to a patient may alsobe determined, as can the temporal requirements for administering eachagent to provide a detectable therapeutic benefit to the patient.Accordingly, while certain dose and administration regimens areexemplified herein, these examples in no way limit the dose andadministration regimen that may be provided to a patient in practicingthe present invention.

It is to be noted that dosage values may vary with the type and severityof the condition to be alleviated, and may include single or multipledoses. It is to be further understood that for any particular subject,specific dosage regimens should be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Forexample, doses may be adjusted based on pharmacokinetic orpharmacodynamic parameters, which may include clinical effects such astoxic effects and/or laboratory values. Thus, the present inventionencompasses intra-patient dose-escalation as determined by the skilledartisan. Determining appropriate dosages and regimens for administrationof the chemotherapeutic agent are well-known in the relevant art andwould be understood to be encompassed by the skilled artisan onceprovided the teachings disclosed herein.

The amount of the compound of the invention administered will bedependent on the subject being treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. However, an effectivedosage is in the range of about 0.001 to about 100 mg per kg body weightper day, preferably about 1 to about 35 mg/kg/day, in single or divideddoses. For a 70 kg human, this would amount to about 0.05 to about 7g/day, preferably about 0.1 to about 2.5 g/day. In some instances,dosage levels below the lower limit of the aforesaid range may be morethan adequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

Formulations and Routes of Administration

As used herein, a “pharmaceutically acceptable carrier” refers to acarrier or diluent that does not cause significant irritation to anorganism and does not abrogate the biological activity and properties ofthe administered compound.

The pharmaceutical acceptable carrier may comprise any conventionalpharmaceutical carrier or excipient. The choice of carrier and/orexcipient will to a large extent depend on factors such as theparticular mode of administration, the effect of the carrier orexcipient on solubility and stability, and the nature of the dosageform.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents (such as hydrates and solvates). Thepharmaceutical compositions may, if desired, contain additionalingredients such as flavorings, binders, excipients and the like. Thusfor oral administration, tablets containing various excipients, such ascitric acid may be employed together with various disintegrants such asstarch, alginic acid and certain complex silicates and with bindingagents such as sucrose, gelatin and acacia.

Examples, without limitation, of excipients include calcium carbonate,calcium phosphate, various sugars and types of starch, cellulosederivatives, gelatin, vegetable oils and polyethylene glycols.Additionally, lubricating agents such as magnesium stearate, sodiumlauryl sulfate and talc are often useful for tableting purposes. Solidcompositions of a similar type may also be employed in soft and hardfilled gelatin capsules. Non-limiting examples of materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution suspension, for parenteral injection as asterile solution, suspension or emulsion, for topical administration asan ointment or cream or for rectal administration as a suppository.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms may be suitably buffered, if desired.

The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages.

Pharmaceutical compositions suitable for the delivery of compounds ofthe invention and methods for their preparation will be readily apparentto those skilled in the art. Such compositions and methods for theirpreparation can be found, for example, in ‘Remington's PharmaceuticalSciences’, 19th Edition (Mack Publishing Company, 1995), the disclosureof which is incorporated herein by reference in its entirety.

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules containing particulates, liquids, or powders,lozenges (including liquid-filled), chews, multi- and nano-particulates,gels, solid solution, liposome, films (including muco-adhesive), ovules,sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be used as fillers in soft or hard capsules andtypically include a carrier, for example, water, ethanol, polyethyleneglycol, propylene glycol, methylcellulose, or a suitable oil, and one ormore emulsifying agents and/or suspending agents. Liquid formulationsmay also be prepared by the reconstitution of a solid, for example, froma sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen(2001), the disclosure of which is incorporated herein by reference inits entirety.

For tablet dosage forms, depending on dose, the drug may make up from 1wt % to 80 wt % of the dosage form, more typically from 5 wt % to 60 wt% of the dosage form. In addition to the drug, tablets generally containa disintegrant. Examples of disintegrants include sodium starchglycolate, sodium carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, lower alkyl-substitutedhydroxypropyl cellulose, starch, pregelatinized starch and sodiumalginate. Generally, the disintegrant will comprise from 1 wt % to 25 wt%, preferably from 5 wt % to 20 wt % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally include surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents are typically inamounts of from 0.2 wt % to 5 wt % of the tablet, and glidants typicallyfrom 0.2 wt % to 1 wt % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallyare present in amounts from 0.25 wt % to 10 wt %, preferably from 0.5 wt% to 3 wt % of the tablet.

Other conventional ingredients include anti-oxidants, colorants,flavoring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80 wt % drug, from about 10 wt %to about 90 wt % binder, from about 0 wt % to about 85 wt % diluent,from about 2 wt % to about 10 wt % disintegrant, and from about 0.25 wt% to about 10 wt % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tableting. The finalformulation may include one or more layers and may be coated oruncoated, or encapsulated.

The formulation of tablets is discussed in detail in “PharmaceuticalDosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, MarcelDekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the disclosure of whichis incorporated herein by reference in its entirety.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations are described in U.S. Pat. No.6,106,864. Details of other suitable release technologies such as highenergy dispersions and osmotic and coated particles can be found inVerma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). Theuse of chewing gum to achieve controlled release is described in WO00/35298. The disclosures of these references are incorporated herein byreference in their entireties.

Parenteral Administration

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilization, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of the invention used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents.

Formulations for parenteral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease. Thus compounds of the invention may be formulated as a solid,semi-solid, or thixotropic liquid for administration as an implanteddepot providing modified release of the active compound. Examples ofsuch formulations include drug-coated stents and PGLA microspheres.

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibers, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may be incorporated;see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan(October 1999). Other means of topical administration include deliveryby electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. Thedisclosures of these references are incorporated herein by reference intheir entireties.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomizer (preferably anatomizer using electrohydrodynamics to produce a fine mist), ornebulizer, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may include a bioadhesive agent, for example,chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilizing, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronized to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters andcartridges for use in an inhaler or insufflator may be formulated tocontain a powder mix of the compound of the invention, a suitable powderbase such as lactose or starch and a performance modifier such asI-leucine, mannitol, or magnesium stearate. The lactose may be anhydrousor in the form of the monohydrate, preferably the latter. Other suitableexcipients include dextran, glucose, maltose, sorbitol, xylitol,fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μL to 100 μL. A typical formulation includes acompound of the invention, propylene glycol, sterile water, ethanol andsodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example,poly(DL-lactic-coglycolic acid (PGLA). Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing a desired mount of the compound of theinvention. The overall daily dose may be administered in a single doseor, more usually, as divided doses throughout the day.

Compounds of the invention may be administered rectally or vaginally,for example, in the form of a suppository, pessary, or enema. Cocoabutter is a traditional suppository base, but various alternatives maybe used as appropriate.

Formulations for rectal/vaginal administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Compounds of the invention may also be administered directly to the eyeor ear, typically in the form of drops of a micronized suspension orsolution in isotonic, pH-adjusted, sterile saline. Other formulationssuitable for ocular and aural administration include ointments,biodegradable (e.g. absorbable gel sponges, collagen) andnon-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

Other Technologies Compounds of the invention may be combined withsoluble macromolecular entities, such as cyclodextrin and suitablederivatives thereof or polyethylene glycol-containing polymers, in orderto improve their solubility, dissolution rate, taste-masking,bioavailability and/or stability for use in any of the aforementionedmodes of administration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubilizer.

Most commonly used for these purposes are alpha-, beta- andgamma-cyclodextrins, examples of which may be found in PCT PublicationNos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of whichare incorporated herein by reference in their entireties.

Dosage

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage istypically in the range of about 0.001 to about 100 mg per kg body weightper day, preferably about 0.01 to about 35 mg/kg/day, in single ordivided doses. For a 70 kg human, this would amount to about 0.07 toabout 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger doses maybe used without causing any harmful side effect, with such larger dosestypically divided into several smaller doses for administrationthroughout the day.

Kit-of-Parts

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.Thus the kit of the invention includes two or more separatepharmaceutical compositions, at least one of which contains a compoundof the invention, and means for separately retaining said compositions,such as a container, divided bottle, or divided foil packet. An exampleof such a kit is the familiar blister pack used for the packaging oftablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically includes directions foradministration and may be provided with a memory aid.

Combination Therapy

As used herein, the term “combination therapy” refers to theadministration of a compound of the invention together with an at leastone additional pharmaceutical or medicinal agent (e.g., an anti-canceragent), either sequentially or simultaneously.

As noted above, the compounds of the invention may be used incombination with one or more additional anti-cancer agents. The efficacyof the compounds of the invention in certain tumors may be enhanced bycombination with other approved or experimental cancer therapies, e.g.,radiation, surgery, chemotherapeutic agents, targeted therapies, agentsthat inhibit other signaling pathways that are dysregulated in tumors,and other immune enhancing agents, such as PD-1 antagonists and thelike.

When a combination therapy is used, the one or more additionalanti-cancer agents may be administered sequentially or simultaneouslywith the compound of the invention. In one embodiment, the additionalanti-cancer agent is administered to a mammal (e.g., a human) prior toadministration of the compound of the invention. In another embodiment,the additional anti-cancer agent is administered to the mammal afteradministration of the compound of the invention. In another embodiment,the additional anti-cancer agent is administered to the mammal (e.g., ahuman) simultaneously with the administration of the compound of theinvention.

The invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human, whichcomprises an amount of a compound of the invention, as defined above(including hydrates, solvates and polymorphs of said compound orpharmaceutically acceptable salts thereof), in combination with one ormore (preferably one to three) anti-cancer therapeutic agents.

In particular embodiments, a compound of the invention may beadministered in combination with one or more: targeted agents, such asinhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF,FLT3, AXL, ROR2, EGFR, FGFR, Src/Abl, RTK/Ras, Myc, Raf, PDGF, AKT,c-Kit, erbB, CDK4/CDK6, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2or Hsp90, or immunomodulatory agents, such as PD-1 or PD-L1 antagonists,OX40 agonists or 4-1 BB agonists.

In other embodiments, a compound of the invention may be administered incombination with a standard of care agent, such as tamoxifen, docetaxel,paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine,exemestane, letrozole, fulvestrant, anastrozole or trastuzumab.

Synthetic Methods

Compounds of the invention are prepared according to the exemplaryprocedures provided herein and modifications thereof known to those ofskill in the art.

The following abbreviations are used throughout the Examples: “Ac” meansacetyl, “AcO” or “OAc” means acetoxy, “ACN” means acetonitrile, “aq”means aqueous, “atm” means atmosphere(s), “BOC”, “Boc” or “boc” meansN-tert-butoxycarbonyl, “Bn” means benzyl, “Bu” means butyl, “nBu” meansnormal-butyl, “tBu” means tert-butyl, “DBU” means1,8-diazabicyclo[5.4.0]undec-7-ene, “Cbz” means benzyloxycarbonyl, “DCM”(CH₂Cl₂) means methylene chloride, “de” means diastereomeric excess,“DEA” means diethylamine, “DIPEA” means diisopropyl ethyl amine, “DMA”means N,N-dimethylacetamide, “DME” means 1,2-dimethoxyethane, “DMF”means N,N-dimethyl formamide, “DMSO” means dimethylsulfoxide, “EDTA”means ethylenediaminetetraacetic acid, “ee” means enantiomeric excess,“Et” means ethyl, “EtOAc” means ethyl acetate, “EtOH” means ethanol,“HOAc” or “AcOH” means acetic acid, “i-Pr” or “^(i)Pr” means isopropyl,“IPA” means isopropyl alcohol, “LAH” means lithium aluminum hydride,“LHMDS” means lithium hexamethyldisilazide (lithiumbis(trimethylsilyl)amide), “mCPBA” means meta-chloroperoxy-benzoic acid,“Me” means methyl, “MeOH” means methanol, “MS” means mass spectrometry,“MTBE” means methyl tert-butyl ether, “NCS” means N-chlorosuccinimide,“Ph” means phenyl, “TBHP” means tert-butyl hydroperoxide, “TFA” meanstrifluoroacetic acid, “THF” means tetrahydrofuran, “SFC” meanssupercritical fluid chromatography, “TLC” means thin layerchromatography, “Rf” means retention fraction, “˜” means approximately,“rt” means retention time, “h” means hours, “min” means minutes, “equiv”means equivalents, “sat.” means saturated.

Preparation of Synthetic Intermediates Intermediate 1:(±)-4-{[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde

A solution of 1-methyl-6-oxabicyclo[3.1.0]hexane (CAS #16240-42-9, 330g, 3.36 mol) in ammonium hydroxide (28 wt % in water, 1.5 L) was stirredat 85° C. for 24 h. The solution was concentrated to a brown gum, thegum dissolved in water (2.0 L) and THE (200 mL), and the solution cooledto 0° C. Sodium hydroxide (287 g, 7.16 mol) and benzyl chloroformate(587 g, 3.44 mol) were added dropwise. The resulting mixture was stirredat room temperature for 18 h, then extracted with DCM (1000 mL×3). Thecombined organic layers were washed with sat. aq NaCl (500 mL), driedover sodium sulfate, and concentrated. The residue was purified bysilica gel chromatography (eluting with 10-33% EtOAc in petroleumether), to give a yellow solid (550 g, 77% pure by NMR). This solid waswashed by petroleum ether/EtOAc (3000 mL/100 mL) and petroleumether/MTBE (2000 mL/500 mL) to give (±)-benzyl[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]carbamate (1a, 239 g, 28%, 90%pure by NMR) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.37(t, J=3.9 Hz, 5H), 5.16-4.95 (m, 3H), 4.44 (s, 1H), 3.81-3.68 (m, 1H),2.15-1.99 (m, 1H), 1.59 (br s, 4H), 1.45-1.31 (m, 1H), 1.19-1.11 (m,3H).

A solution of (±)-benzyl[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]carbamate (1a, (109 g, 437mmol) in MeOH (1000 mL) was treated with wet Pd/C (11 g). The blacksuspension was stirred at 20° C. under hydrogen (20 psi) for 18 h. Afterremoval of the solids by filtration, the filtrate was concentrated togive (±)-(1R*,2R*)-2-amino-1-methylcyclopentanol (1b, 48.0 g, 95%) as apale yellow gum. ¹H NMR (400 MHz, DMSO-d₆) δ=2.86 (t, J=6.9 Hz, 1H),1.99-1.86 (m, 1H), 1.60-1.49 (m, 4H), 1.28-1.17 (m, 1H), 1.08 (s, 3H).

A solution of [4-chloro-2-(methylsulfanyl)pyrimidin-5-yl]methanol (CAS#1044145-59-6, 6.6 g, 35 mmol),(±)-(1R*,2R*)-2-amino-1-methylcyclopentanol (1b, 4.4 g, 46 mmol) andtriethylamine (14.5 mL, 104 mmol) in ACN (86 mL) was stirred in a 50° C.oil bath for 16 h. The reaction solution was evaporated to dryness.Water (25 mL), sat. aq NaCl (25 mL) and sat. aq NaHCO₃ (25 mL) wereadded to the residue, and the mixture extracted with EtOAc (200 mL×3).The combined organics were dried over sodium sulfate, and concentratedto dryness. The residue (9.3 g light yellow gum) was suspended in EtOAc(50 mL) with sonication to produce a thick white slurry. This slurry washeated at 60° C. with stirring. Heptane (˜150 mL) was added slowly tothe heated suspension, then the mixture allowed to cool to roomtemperature overnight. The resulting solid was collected by filtration,rinsed with heptane (30 mL), and dried to give(±)-(1R*,2R*)-2-{[5-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1-methylcyclopentanol(1c, 6.91 g, 74%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.82 (s,1H), 6.32 (d, J=7.9 Hz, 1H), 5.27 (t, J=5.4 Hz, 1H), 4.66 (s, 1H), 4.36(d, J=5.3 Hz, 2H), 4.30 (q, J=7.7 Hz, 1H), 2.42 (s, 3H), 2.22-2.10 (m,1H), 1.75-1.56 (m, 4H), 1.52-1.39 (m, 1H), 1.09 (s, 3H). MS: 270 [M+H]⁺.

Manganese dioxide (33.4 g, 384 mmol) was added to a suspension of(±)-(1R*,2R*)-2-{[5-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1-methylcyclopentanol(1c, 6.9 g, 25.6 mmol) in EtOAc (384 mL), and the mixture stirred in a50° C. oil bath for 7 h, and then at room temperature overnight. Solidswere removed by filtration. The flask and filter cake were washed withEtOAc (˜300 mL). The combined filtrates were filtered again to remove asmall amount of residual black solid, then concentrated to give(±)-4-{[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylsulfanyl)-pyrimidine-5-carbaldehyde(Intermediate 1, 5.84 g, 85%) as an off-white solid. ¹H NMR (400 MHz,CDCl₃) δ=9.72 (s, 1H), 8.66 (br s, 1H), 8.35 (s, 1H), 4.39 (ddd, J=6.5,8.2, 9.5 Hz, 1H), 4.15 (br s, 1H), 2.57 (s, 3H), 2.33-2.23 (m, 1H),2.03-1.92 (m, 1H), 1.91-1.70 (m, 3H), 1.68-1.56 (m, 1H), 1.17 (s, 3H).MS: 268 [M+H]⁺.

Intermediate 2:4-{[(1R,2R)-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylsulfanyl)-pyrimidine-5-carbaldehyde

A 150 mL sealable flask was charged with water (50.9 mL) and benzylamine(10.9 g, 11.1 mL, 102 mmol), then purged with nitrogen for 5 min, before1-methyl-6-oxabicyclo[3.1.0]hexane (CAS #16240-42-9, 10 g, 102 mmol) wasadded. The flask was sealed and heated at 100° C. for 18 h, at whichtime a biphasic mixture was observed. After cooling to room temperaturethe flask was further cooled in an ice-water bath. Concentrated aqueousHCl (˜12 M, 13 mL) was added to bring the pH to 1. The organicimpurities were extracted with EtOAc (150 mL) and set aside. The acidicaqueous layer was cooled in an ice-water bath and adjusted to pH 10using 5N aq NaOH. The resulting biphasic mixture was extracted withEtOAc (250 mL×3). The combined organic extracts were dried over sodiumsulfate and concentrated to a brown oil. The remaining benzylamine wasevaporated under higher vacuum (˜5 mmHg) at 80° C. for several h, until¹HNMR of a sample showed only ˜20 mole % benzylamine remaining. Theresidual oil was triturated with heptane (100 mL), causing whitecrystals to form. The crystals were collected by filtration and dried togive (±)-(1R*,2R*)-2-(benzylamino)-1-methylcyclopentanol (2a, 13 g, 62%)as a white crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ=7.36-7.31 (m,4H), 7.28-7.23 (m, 1H), 3.91-3.85 (m, 1H), 3.79-3.74 (m, 1H), 2.86 (dd,J=7.8, 8.5 Hz, 1H), 2.12-2.03 (m, 1H), 1.75-1.53 (m, 5H), 1.37-1.27 (m,1H), 1.22 (s, 3H).

A magnetically-stirred solution of(±)-(1R*,2R*)-2-(benzylamino)-1-methylcyclopentanol (2a, 100 g, 487mmol) and EtOH (700 mL) in a 1 L flask was heated in an 80° C. oil bathfor 30 min. A separate 5 L, three-neck flask equipped with an overheadstirrer, internal thermometer, and water-cooled condenser was chargedwith (2S)-[(3,5-dinitrobenzoyl)amino](phenyl)ethanoic acid (CAS#74927-72-3, 84.1 g, 244 mmol, 0.5 equiv) and EtOH (1.4 L). This flaskwas also heated in an 80° C. oil bath with stirring until the soliddissolved, ˜15 min, and stirring continued for another 30 min. The hotsolution of amine 2a from the first flask was poured via funnel, in asteady flow over 1 min, into the hot, mechanically stirred solution ofchiral acid in the second flask. The transfer was quantitated with EtOH(10 mL). The reaction mixture remained clear for about 1 min, thenprecipitation began. After 5 min, a thick white suspension had formed,but did not hinder mechanical stirring. Stirring was continued at 80° C.for 4 h, then heating was discontinued and the mixture was stirred whilegradually cooling to room temperature overnight. The resulting solid wascollected by filtration, washed with EtOH (350 mL), and dried in avacuum oven (10 mmHg, 40° C.) for 1.5 days, affording(1R,2R)—N-benzyl-2-hydroxy-2-methylcyclopentanaminium(2S)-[(3,5-dinitrobenzoyl)amino](phenyl)acetate (2b-RR, 110.22 g, 82%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.64 (d, J=7.0 Hz, 1H),9.09 (d, J=2.1 Hz, 2H), 8.96 (t, J=2.1 Hz, 1H), 7.55-7.48 (m, 2H),7.43-7.23 (m, 8H), 5.47 (d, J=7.1 Hz, 1H), 4.02-3.75 (m, 2H), 2.86 (t,J=8.0 Hz, 1H), 2.03-1.87 (m, 1H), 1.66-1.48 (m, 4H), 1.48-1.32 (m, 1H),1.17 (s, 3H). MS: 206 [M+H]⁺ for amine cation. A small-molecule X-raycrystal structure of this salt confirmed absolute (1R,2R)stereochemistry on the cyclopentane ring.

The chiral salt (1R,2R)—N-benzyl-2-hydroxy-2-methylcyclopentanaminium(2S)-[(3,5-dinitrobenzoyl)amino](phenyl)acetate (2b-RR, 110.22 g, 200.2mmol) was suspended in water (500 mL) and EtOAc (700 mL) in a 2 Lseparatory funnel. Aqueous HCl (4 M, 200 mL, 800 mmol) was added and themixture agitated for ˜30 seconds. A clear biphasic mixture was obtained.The layers were separated, and the organic layer was further washed withaqueous HCl (0.2 M, 125 mL×2). The acidic aqueous layers were combined,split into two portions, and each portion cooled in an ice-water bath.Aqueous NaOH (4 N, 150 mL, 600 mmol) was added to each portion to bringthe pH to 10. A white suspension formed at this pH. The two portionswere combined, diluted with sat. aq NaCl (150 mL), and extracted withEtOAc (250 mL×4). The combined organic extracts were dried over sodiumsulfate and evaporated to give(1R,2R)-2-(benzylamino)-1-methylcyclopentanol (2b-00, 41.4 g, 100%, 96%ee). ¹H NMR (400 MHz, DMSO-d₆) δ=7.36-7.25 (m, 4H), 7.24-7.16 (m, 1H),4.23 (s, 1H), 3.78-3.65 (m, 2H), 2.70 (t, J=7.5 Hz, 1H), 1.86 (dt,J=3.9, 7.8 Hz, 1H), 1.73 (br s, 1H), 1.62-1.44 (m, 4H), 1.35-1.23 (m,1H), 1.12 (s, 3H). Chiral purity: 96% ee. Chiral SFC/MS analysis wasperformed on a Chiralpak AS-3, 4.6×100 mm, 3 μm column heated to 25° C.and eluted with a mobile phase of CO₂ and 5% diethylamine in ethanol (20mM v/v) in 1 min flowing at 3.5 mL/min and maintained at 160 bar outletpressure. A gradient to 50% modifier in 3 min was added to elute anyremaining counter ions. The detection was APCI(+)MS monitored from100-800 Da with single ion monitoring (SIM) at 206 Da. The product peakhad a retention time of 1.81 min. Optical rotation of a sample made bythis method gave [α]_(D) ²²−42.6 (c 1.0, MeOH).

Since higher chiral purity was desired, the classical resolution wasrepeated on the enantio-enriched amine: A solution of(1R,2R)-2-(benzylamino)-1-methylcyclopentanol (2b-00, (41.0 g, 200 mmol,96% ee) in EtOH (200 mL) was heated at 80° C. with stirring for 30minutes. A separate 2 L, three-necked flask equipped with an overheadstirrer, internal thermometer and water-cooled condenser was chargedwith (2S)-[(3,5-dinitrobenzoyl)amino](phenyl)ethanoic acid (CAS#74927-72-3, 67 g, 194 mmol, 0.97 equiv; since amine was ˜96% ee) andEtOH (1.3 L). This flask was stirred and heated at 80° C. (internal)until the solid dissolved (˜15 min) then for 30 min more. The hot aminesolution was added to the hot acid solution through a funnel in a steadyflow (less than 1 min), and the transfer quantitated with EtOH (10 mL).Precipitation began in about 1 min, and by 5 min a thick whitesuspension had formed, though stirring was not hindered. Stirring wascontinued at 80° C. for 4 h, then heating was discontinued and thereaction stirred and allowed to gradually cool to room temperatureovernight. The resulting solid was collected by filtration, washed withEtOH (350 mL) and dried (10 mmHg, 40° C.) for 1.5 days to give(1R,2R)—N-benzyl-2-hydroxy-2-methylcyclopentanaminium(2S)-[(3,5-dinitrobenzoyl)amino](phenyl)acetate (2b-RR, 106 g, 99%). ¹HNMR (400 MHz, DMSO-d₆) δ=9.66 (d, J=7.0 Hz, 1H), 9.09 (d, J=2.1 Hz, 2H),8.96 (t, J=2.1 Hz, 1H), 7.55-7.46 (m, 2H), 7.44-7.22 (m, 8H), 5.48 (d,J=7.1 Hz, 1H), 4.63 (br s, 1H), 3.96-3.79 (m, 2H), 3.66-2.97 (m, 2H),2.84 (t, J=7.9 Hz, 1H), 2.00-1.85 (m, 1H), 1.64-1.48 (m, 4H), 1.45-1.32(m, 1H), 1.16 (s, 3H). MS: 206 [M+H]⁺ for amine cation.

A stirred suspension of(1R,2R)—N-benzyl-2-hydroxy-2-methylcyclopentanaminium(2S)-[(3,5-dinitrobenzoyl)amino](phenyl)acetate (2b-RR, 106 g, 193 mmol)in water (500 mL) and EtOAc (700 mL) was treated with aq HCl (4 M, 193mL, 770 mmol) and agitated for ˜30 seconds. A clear biphasic mixture wasobtained. The layers were separated, and the aqueous layer was extractedwith more EtOAc (125 mL×2). The organic layers were set aside. Theacidic aqueous layer was cooled in an ice-water bath, and basified to pH10 with aq NaOH (4 N, 289 mL, 6 equiv, 1160 mmol). The resulting whitesuspension was diluted with sat. aq NaCl (300 mL) and extracted withEtOAc (700 mL×4). The combined organic extracts were dried over sodiumsulfate, and evaporated to give(1R,2R)-2-(benzylamino)-1-methylcyclopentanol (2b-00, 38.5 g, 97%, 98%ee). ¹H NMR (400 MHz, CDCl₃) δ=7.38-7.30 (m, 4H), 7.27-7.23 (m, 1H),3.94-3.75 (m, 2H), 2.88 (dd, J=7.8, 8.4 Hz, 1H), 2.16-2.03 (m, 1H),1.79-1.57 (m, 4H), 1.53-1.39 (m, 2H), 1.38-1.28 (m, 1H), 1.25 (s, 3H).MS: 206 [M+H]⁺. Chiral purity: 98% ee. Chiral SFC/MS analysis wasperformed on a Chiralpak AS-3, 4.6×100 mm, 3 μm column heated to 25° C.and eluted with a mobile phase of CO₂ and 5% diethylamine in ethanol (20mM v/v) in 1 min flowing at 3.5 mL/min and maintained at 160 bar outletpressure. A gradient to 50% modifier in 3 min was added to elute anyremaining counter ions. The detection was APCI(+)MS monitored from100-800 Da with single ion monitoring (SIM) at 206 Da. The product peakhad a retention time of 1.82 min. Optical rotation of this batch was notdetermined.

To a nitrogen-filled 3-L three-necked flask was added 20%-Pd(OH)₂/C(Aldrich 212911-10G, Lot #SHBC7570V, 3.85 g) and 2-propanol (260 mL). Asolution of (1R,2R)-2-(benzylamino)-1-methylcyclopentanol (2b-00, 38.5g, 188 mmol, 98% ee) in 2-propanol (1300 mL) was added. The transfer wasquantitated with 2-propanol (30 mL). The solution was purged withhydrogen gas for ˜2 min, and then stirred at room temperature under ahydrogen atmosphere (three balloons) for 16 h. The balloons werereplenished with hydrogen and stirring continued at room temperature for6 h, at which time ¹H NMR of an aliquot indicated the reaction wascomplete. The reaction mixture was purged with nitrogen, and thecatalyst removed by filtration through a Celite® cake. The flask andfilter cake were washed with 2-propanol (500 mL). A small aliquot of thecombined filtrate was evaporated for analysis. The remainder of thefiltrate was concentrated under reduced pressure (˜10 mmHg, 20° C.) toabout 350 mL, and the crude (1R,2R)-2-amino-1-methylcyclopentanol (2c)used directly in the next step without further purification. ¹H NMR (400MHz, CDCl₃) δ=3.03 (t, J=7.4 Hz, 1H), 2.19-2.01 (m, 1H), 1.83-1.58 (m,4H), 1.42 (s, 3H), 1.35-1.25 (m, 1H), 1.22 (s, 3H). MS: 116 [M+H]⁺.Chiral SFC analysis: 96% ee. Chiral SFC/MS analysis was performed on aChiroSil RCA (+), 4.6×150 mm 5p column heated to 40° C. and eluted witha mobile phase of 20% ACN, 60% formic Acid in MeOH (1% v/v), 20%ammonium formate in MeOH (20 mM w/v) flowing at 1.5 mL/min. Thedetection was ESI (+) MS monitored from 100-650 Da with single ionmonitoring (SIM) at 116 Da. The product peak had a retention time of2.09 min. Optical rotation of a previous batch made by this method gave[α]_(D) ²²−37.7 (c 0.3, MeOH).

To the crude solution of (1R,2R)-2-amino-1-methylcyclopentanol (2c, 188mmol theoretical) in 2-propanol (˜350 mL) was added solid[4-chloro-2-(methylsulfanyl)pyrimidin-5-yl]methanol (CAS #1044145-59-6,34.8 g, 182 mmol) and DIPEA (95.3 mL, 547 mmol). The mixture wasdegassed with nitrogen and stirred under a nitrogen atmosphere at roomtemperature for 15 min, then at 80° C. for 40 h. The volatiles wereremoved, and the residual oil (95 g) was partitioned between EtOAc (800mL) and sat. aq NaCl (250 mL). The aq layer was further extracted withEtOAc (500 mL×3). The combined organic extracts were dried over sodiumsulfate and evaporated to give an oil (75 g). This oil was dissolved inEtOAc (200 mL), and the clear solution heated at 60° C. Some white solidwas observed 5 min after initiation of heating. When at 60° C., heptane(400 mL) was slowly added to the suspension, and stirring continued at60° C. for 15 min. The suspension was cooled to room temperature, andthen cooled in an ice-water bath for 15 min. The resulting precipitatewas collected by filtration and dried to give(1R,2R)-2-{[5-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1-methylcyclopentanol(2d, 47.8 g, 97%, 98% ee). ¹H NMR (400 MHz, CDCl₃) δ=7.76 (s, 1H), 6.01(d, J=4.6 Hz, 1H), 5.31 (br s, 1H), 4.55 (s, 2H), 4.26 (ddd, J=5.7, 8.2,10.5 Hz, 1H), 2.50 (s, 3H), 2.21 (ddd, J=3.5, 8.2, 12.1 Hz, 1H), 1.97(dt, J=3.5, 7.7 Hz, 1H), 1.89-1.76 (m, 2H), 1.75-1.63 (m, 1H), 1.60-1.50(m, 2H), 1.11 (s, 3H). MS: 270 [M+H]⁺. Optical rotation: [α]_(D) ²²+37.7(c 1.0, MeOH). Chiral purity: 98% ee. Chiral SFC/MS analysis wasperformed on a Chiralpak IC-3, 4.6×150 mm, 3 μm column heated to 25° C.and eluted with a mobile phase of CO₂ and 30% ammonia in methanol (20 mMv/v) flowing at 4.0 mL/min and maintained at 160 bar outlet pressure.The product peak had a retention time of 1.85 min.

To a 2 L, 3-necked flask equipped with a mechanical stirrer and a refluxcondenser was added solid manganese dioxide (10 μm mesh, reagent grade,278 g, 2660 mmol), EtOAc (1.2 L, 0.14 M) and solid(1R,2R)-2-{[5-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1-methylcyclopentanol(2d, 47.7 g, 177 mmol). The mixture was stirred under nitrogen andheated in a 50° C. oil bath for 4 h. More manganese dioxide (80 g) wasadded; stirring and heating were continued for another 16 h, until thereaction was complete by LCMS. The solid was removed by filtration, andthe flask and filter cake were washed with EtOAc (1 L). The combinedfiltrates were refiltered to completely remove trace insolubles, andthen evaporated to give4-{[(1R,2R)-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 2, 43.8 g, 93%, >98% ee) as a white solid. ¹H NMR (400MHz, CDCl₃) δ=9.73 (s, 1H), 8.66 (br s, 1H), 8.35 (s, 1H), 4.39 (ddd,J=6.5, 8.2, 9.6 Hz, 1H), 4.16 (s, 1H), 2.57 (s, 3H), 2.33-2.22 (m, 1H),2.03-1.92 (m, 1H), 1.89-1.68 (m, 3H), 1.68-1.56 (m, 1H), 1.17 (s, 3H).MS: 268 [M+H]⁺. Optical rotation [α]_(D) ²²+12.7 (c 1.0, CHCl₃). Chiralpurity: >98% ee. Chiral SFC/MS analysis was performed on a ChiralpakIC-3, 4.6×150 mm, 3 μm column heated to 25° C. and eluted with a mobilephase of CO₂ and 30% ammonia in methanol (20 mM v/v) flowing at 4.0mL/min and maintained at 160 bar outlet pressure. The product peak had aretention time of 2.83 min.

Intermediate 3:4-{[(1R,3R)-3-hydroxycyclohexyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde

A solution of [4-chloro-2-(methylsulfanyl)pyrimidin-5-yl]methanol (CAS#1044145-59-6, 3.5 g, 18.4 mmol), (1R,3R)-3-aminocyclohexanol (3.34 g,22.0 mmol) [Brocklehurst, C. E.; Laumen, K.; La Vecchia, L.; Shaw, D.;Vögtle, M. Org. Process Res. Dev. 2011, 15, 294. [α]_(D) ²²−4.9 (c 1.2,MeOH)], and DIPEA (11.9 g, 16.3 mL) in EtOH (40 mL) was stirred at 85°C. for 20 h. After cooling to room temperature, the mixture waspartitioned between water and DCM. The organics were concentrated todryness and purified by silica gel chromatography (eluting with 0-30%MeOH in DCM) to give(1R,3R)-3-{[5-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-4-yl]amino}cyclohexanol(3a, 4.80 g, 97%) as a yellow foam. ¹H NMR (400 MHz, CDCl₃) δ=7.62-7.47(m, 1H), 6.05 (d, J=7.5 Hz, 1H), 4.58-4.31 (m, 3H), 4.02 (br d, J=3.0Hz, 1H), 2.54-2.34 (m, 3H), 1.88-1.71 (m, 4H), 1.70-1.52 (m, 3H), 1.43(br s, 1H). MS: 270 [M+H]⁺. Optical rotation: [α]_(D) ²²+0.14 (c 2.8,MeOH). Chiral purity: >95% ee. Chiral SFC/MS analysis was performed on aChiralpak AD-3, 4.6×150 mm, 3 μm column heated to 40° C. and eluted witha mobile phase of CO₂ and a gradient of 5 to 40% EtOH (0.05% DEA) over5.5 min, flowing at 2.5 mL/min. Flow at 40% EtOH (0.05% DEA) wascontinued for 3 min to elute any remaining counter ions. The productpeak had a retention time of 3.79 min.

A suspension of(1R,3R)-3-{[5-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-4-yl]amino}cyclohexanol(3a, 4.80 g, 17.8 mmol) and manganese dioxide (15.5 g, 178 mmol) inchloroform (70 mL) was stirred at room temperature for 18 h. The mixturewas filtered, the flask and filter cake rinsed with EtOAc (100 mL) andTHF (100 mL), and the combined filtrates concentrated to dryness. Theresidue was purified by silica gel chromatography (eluting with 0-40%EtOAc in petroleum ether) to give4-{[(1R,3R)-3-hydroxycyclohexyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 3, 3.70 g, 80%) as a yellow gum. ¹H NMR (400 MHz, CDCl₃)δ=9.69 (s, 1H), 8.61 (br s, 1H), 8.30 (s, 1H), 4.75-4.49 (m, 1H),4.27-4.01 (m, 1H), 2.56 (s, 3H), 2.00-1.87 (m, 2H), 1.87-1.56 (m, 6H).MS: 268 [M+H]⁺. Optical rotation: [α]_(D) ²²+2.8 (c 1.4, MeOH). Chiralpurity: 96%. Chiral SFC/MS analysis was performed on a Chiralpak AD-3,4.6×150 mm, 3 μm column heated to 40° C. and eluted with a mobile phaseof CO₂ and a gradient of 5 to 40% EtOH (0.05% DEA) over 5.5 min, flowingat 2.5 mL/min. Flow at 40% EtOH (0.05% DEA) was continued for 3 min toelute any remaining counter ions. The product peak had a retention timeof 4.42 min.

Intermediate 4:4-{[(1R,2R)-2-hydroxycyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde

By the same method as Intermediate 3, (1R,2R)-2-aminocyclopentanolhydrochloride (CAS #68327-11-7) was used to produce4-{[(1R,2R)-2-hydroxycyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 4). ¹H NMR (400 MHz, CDCl₃) δ=9.70 (s, 1H), 8.72-8.62 (m,1H), 8.34 (s, 1H), 4.24-4.14 (m, 1H), 4.12-4.02 (m, 1H), 3.97 (s, 1H),2.57 (s, 3H), 2.34-2.21 (m, 1H), 2.13-2.01 (m, 1H), 1.93-1.60 (m, 4H).MS: 254 [M+H]⁺.

Intermediate 5:4-(cycloheptylamino)-2-(methylsulfanyl)pyrimidine-5-carbaldehyde

A suspension of ethyl4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate (CAS #5909-24-0, 16g, 68.7 mmol), cycloheptylamine (9.34 g, 82.5 mmol) and DIPEA (17.8 g,138 mmol) in THE (150 mL) was stirred at room temperature for 18 h.Solvents were evaporated, the residue dissolved in water (150 mL), andthe solution extracted with EtOAc (150 mL×2). The combined organics werewashed with sat. aq NaCl (150 mL×2), dried over sodium sulfate, andconcentrated to give ethyl4-(cycloheptylamino)-2-(methylsulfanyl)pyrimidine-5-carboxylate (5a, 21g, 99%) as yellow oil. MS: 310 [M+H]⁺.

A cooled (5° C.) solution of ethyl4-(cycloheptylamino)-2-(methylsulfanyl)pyrimidine-5-carboxylate (5a, 21g, 67.9 mmol) in THE (200 mL) was treated LAH (2.5 M solution in THF,81.4 mL, 204 mmol) in portions over 1.5 h. The resulting suspensionstirred at 5 to 10° C. for an additional hour, then at room temperaturefor 18 h. The mixture was cooled slightly (15° C.), then water (10 mL)and 2 N NaOH (10 mL) were added dropwise to quench any residual LAH.After stirring for 1 hour at room temperature, the suspension wasfiltered, and the flask and filter cake were rinsed with THE (300 mL×4).The combined filtrates were concentrated to remove most of the solvent.The residue was partitioned between water (100 mL) and EtOAc (250 mL×2).The combined organic layers were washed with sat. aq NaCl (100 mL),dried over sodium sulfate, and concentrated to dryness. The crudeproduct was recrystallized from petroleum ether/EtOAc (200 mL/50 mL) togive [4-(cycloheptylamino)-2-(methylsulfanyl)pyrimidin-5-yl]methanol(5b, 13.6 g, 75%) as a white solid. MS: 268 [M+H]⁺.

Manganese dioxide (43.3 g, 860 mmol) was added to a solution of[4-(cycloheptylamino)-2-(methylsulfanyl)pyrimidin-5-yl]methanol (5b,13.6 g, 50 mmol) in chloroform (200 mL), and the resulting suspensionstirred at room temperature for 15 h. The solids were removed byfiltration. The flask and filter cake were rinsed with DCM (150 mL×4).The combined filtrates were filtered again to remove trace solids, andconcentrated to give4-(cycloheptylamino)-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 5, 12.9 g, 98%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃)δ=9.68 (s, 1H), 8.63 (br s, 1H), 8.28 (s, 1H), 4.36-4.32 (m, 1H), 2.55(s, 3H), 2.03-1.99 (m, 2H), 1.67-1.58 (m, 10H). MS: 266 [M+H]⁺.

Intermediate 6:4-{[(1R,2S)-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde

By the same method as Intermediate 5, (1R,2S)-2-methylcyclopentanamine[Wiehl, W.; Frahm, A. W. Chem. Ber. 1986, 119, 2668] was used to produce4-{[(1R,2S)-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 6). ¹H NMR (400 MHz, CDCl₃) δ=9.70 (s, 1H), 8.67 (br s,1H), 8.29 (s, 1H), 4.65-4.58 (m, 1H), 2.55 (s, 3H), 2.32-2.23 (m, 1H),2.11-2.02 (m, 1H), 1.95-1.77 (m, 2H), 1.70-1.62 (m, 2H), 1.46-1.37 (m,1H), 0.93 (d, J=6.8, 3H). MS: 252 [M+H]⁺.

Intermediate 7: 4-{[(1S,2R)-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde

By the same method as Intermediate 5, (1 S,2R)-2-methylcyclopentanamine[Wiehl, W.; Frahm, A. W. Chem. Ber. 1986, 119, 2668] was used to produce4-{[(1S,2R)-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 7). ¹H NMR (400 MHz, CDCl₃) δ=9.68 (s, 1H), 8.73-8.59 (m,1H), 8.27 (s, 1H), 4.67-4.52 (m, 1H), 2.53 (s, 3H), 2.29-2.20 (m, 1H),2.12-1.99 (m, 1H), 1.92-1.75 (m, 2H), 1.63 (s, 2H), 1.45-1.34 (m, 1H),0.91 (d, J=7.0, 3H). MS: 252 [M+H]⁺.

Intermediate 8:(±)-4-{[(1R*,3R*)-3-hydroxycyclopentyl]amino}-2-(methylsulfanyl)-pyrimidine-5-carbaldehyde

To a cooled (0° C.) solution of(±)-trans-(3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester (2.03g, 10.1 mmol) [Kulagowski, J. J. et al. J. Med. Chem. 2012 55, 5901] in1,4-dioxane (20 mL) was added HCl (4.0 mL solution in 1,4-dioxane, 20mL, 80 mmol), and the mixture stirred at 0° C. for 1 h and at roomtemperature for 3 h. The solvents were evaporated, the residue dissolvedDCM (50 mL), and a solution of NaOH (502.2 mg, 12.6 mmol) in water (1.5mL) was added. After stirring at room temperature for 1 h, the reactionmixture was dried over a mixture of anhydrous sodium carbonate andanhydrous sodium sulfate, filtered, and concentrated to give(±)-trans-(3-hydroxy-cyclopentyl amine (8a, 0.68 g, 67%) as an amberliquid, which was used without further purification in the followingreaction. ¹H NMR (400 MHz, DMSO-d₆) δ=4.29 (br s, 1H), 4.19-4.10 (m,1H), 3.35 (quin, J=6.4 Hz, 1H), 1.93-1.80 (m, 2H), 1.64 (ddd, J=3.4,6.9, 13.0 Hz, 1H), 1.54 (br s, 2H), 1.41-1.32 (m, 2H), 1.19-1.07 (m,1H).

A solution of 4-chloro-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(613.7 mg, 3.25 mmol) [Zheng, K.; Min Park, C.; Iqbal, S. Hernandez, P.;Park, H.; LoGrasso, P. V.; Feng, Y. ACS Med. Chem. Lett. 2015, 6, 413],(±)-trans-(3-hydroxy-cyclopentyl amine (8a, 0.68 g, 6.7 mmol), and DIPEA(3.0 mL, 17 mmol) in EtOH (32.5 mL) was heated in a 70° C. oil bath for18 h. Solvents were evaporated and the residue partitioned between sat.aq NaHCO₃ (50 mL) and EtOAc (50 mL×3). The combined organic layers weredried over magnesium sulfate, filtered, and concentrated. The browngummy residue was dissolved in ACN (20 mL), causing a precipitate toform. The slurry was concentrated to dryness, leaving crude iminediadduct (8b, 0.90 g, 82%) as a dark yellow solid, with minorimpurities. ¹H NMR (400 MHz, DMSO-d₆) δ=9.96 (d, J=6.8 Hz, 1H), 8.29 (s,1H), 8.14 (s, 1H), 4.60 (d, J=3.9 Hz, 1H), 4.58 (d, J=3.9 Hz, 1H), 4.51(sxt, J=6.8 Hz, 1H), 4.34-4.27 (m, 1H), 4.26-4.19 (m, 1H), 3.88 (quin,J=6.0 Hz, 1H), 2.47 (s, 3H), 2.25-2.14 (m, 1H), 2.10-1.78 (m, 5H),1.77-1.68 (m, 1H), 1.63-1.45 (m, 4H), 1.38 (tdd, J=6.2, 8.7, 12.7 Hz,1H).

The crude imine diadduct (8b, 0.90 g) was dissolved in THE (20 mL) andtreated with HCl (4.0 M solution in 1,4-dioxane, 4.1 mL, 16.4 mmol). Alight-colored precipitate formed immediately on contact with the acid,hindering stirring. More THE (10 mL) was added and the mixture manuallyshaken and sonicated until stirring could be re-established, thencontinued stirring at room temperature for 2 h. The reaction mixture wasdiluted with EtOAc (50 mL). While stirring, sat. aq NaHCO₃ (30 mL) wasadded dropwise, causing mild gas evolution. The layers of the resultingclear, biphasic solution were separated and the aqueous layer furtherextracted with EtOAc (50 mL). The combined organic layers were driedover magnesium sulfate, filtered, and concentrated to give(±)-4-{[(1R*,3R*)-3-hydroxycyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 8, 659.9 mg, 74% from4-chloro-2-(methylsulfanyl)pyrimidine-5-carbaldehyde) as a brown oil. ¹HNMR (400 MHz, DMSO-d₆) δ=9.74 (s, 1H), 8.52 (s, 1H), 8.54 (br s, 1H),4.72-4.61 (m, 1H), 4.59 (d, J=3.8 Hz, 1H), 4.28-4.19 (m, 1H), 2.52 (s,3H), 2.26-2.14 (m, 1H), 2.04-1.88 (m, 2H), 1.66 (ddd, J=5.9, 7.8, 13.4Hz, 1H), 1.58-1.41 (m, 2H). MS: 254 [M+H]⁺.

Intermediate 9: 4-amino-N-methylpiperidine-1-sulfonamide

A solution of benzyl 4-piperidinylcarbamate (CAS #182223-54-7, 7.0 g, 27mmol) and triethylamine (3.27 g, 32.3 mmol) in DCM (80 mL) was added toa chilled (0° C.) solution of sulfuryl chloride (3.99 g, 29.6 mmol) inDCM (70 mL), slowly enough to keep the internal temperature below 10° C.The cooling bath was removed and the mixture stirred at room temperaturefor 2 h. The reaction mixture was cooled again to 0° C., then a solutionof methylamine (2.0 M in THF, 26.9 mL, 53.8 mmol) and more triethylamine(15 mL, 108 mmol) in DCM (50 mL) was added dropwise, keeping theinternal temperature below 10° C. The resulting suspension was stirredat room temperature for 15 h. Because LCMS indicated the presence ofresidual chlorosulfonyl intermediate, the solution was cooled to 0° C.and more methylamine (2.0 M in THF, 40 mL, 80 mmol) added. Stirring wascontinued at room temperature for 3 h, at which time no chlorosulfonylintermediate could be detected by LCMS. The reaction was partitionedbetween water (100 mL) and DCM (150 mL×2). The combined organic extractswere dried, concentrated, and purified by silica gel chromatography(eluting with 50-80% EtOAc in petroleum ether) to give benzyl[1-(methylsulfamoyl)piperidin-4-yl]carbamate (9a, 4.0 g, 90% purity, 45%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=7.42-7.31 (m, 5H),5.17-5.06 (m, 2H), 4.73 (d, J=6.5 Hz, 1H), 4.12 (q, J=4.9 Hz, 1H), 3.67(d, J=12.3 Hz, 3H), 2.97-2.88 (m, 2H), 2.72 (d, J=5.3 Hz, 3H), 2.03 (d,J=11.3 Hz, 2H), 1.57-1.46 (m, 2H). MS: 350 [M+Na]⁺.

A suspension of benzyl [1-(methylsulfamoyl)piperidin-4-yl]carbamate (9a,4.0 g, 12 mmol) and Pd/C (50% H₂O, 2 g) in THF (100 mL) was deoxygenatedand purged with hydrogen (3 cycles), then stirred under a hydrogenballoon at room temperature for 4 h. The suspension was filtered, andthe filtrate concentrated to give crude product (2.3 g, 85% purity, 100%yield) as a white solid.

Multiple batches made by this method were combined to give 45 g of crudeproduct, which was then recrystallized from hot DCM to give pure4-amino-N-methylpiperidine-1-sulfonamide (Intermediate 9, 40 g, 89%). ¹HNMR (400 MHz, DMSO-d₆) δ=3.45-3.37 (m, 2H), 2.75-2.59 (m, 3H), 2.50 (s,3H), 1.78-1.67 (m, 2H), 1.30-1.15 (m, 2H). MS: 194 [M+H]⁺.

Intermediate 10:4-amino-N-(2-methoxy-2-methylpropyl)piperidine-1-sulfonamide

By the method of Intermediate 9, 2-methoxy-2-methylpropan-1-amine wasused to synthesize4-amino-N-(2-methoxy-2-methylpropyl)piperidine-1-sulfonamide(Intermediate 10). ¹H NMR (400 MHz, CDCl₃) δ=4.54-4.42 (m, 1H), 3.67 (d,J=12.3 Hz, 2H), 3.19 (s, 3H), 3.01 (d, J=5.8 Hz, 2H), 2.88-2.76 (m, 3H),1.89 (d, J=10.5 Hz, 2H), 1.39 (d, J=9.3 Hz, 2H), 1.21 (s, 6H)

Intermediate 11:4-amino-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-sulfonamide

By the method of Intermediate 9, 4-aminotetrahydropyran was used tosynthesize the compound4-amino-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-sulfonamide(Intermediate 11). ¹H NMR (400 MHz, CDCl₃) δ=4.24-4.13 (m, 1H), 3.95(td, J=3.6, 11.7 Hz, 2H), 3.77-3.74 (m, 1H), 3.67 (d, J=12.5 Hz, 2H),3.43 (dt, J=2.3, 11.7 Hz, 3H), 2.89-2.77 (m, 3H), 2.02-1.86 (m, 5H),1.59-1.48 (m, 2H), 1.46-1.38 (m, 3H) Other4-amino-N-alkyl-piperidine-1-sulfonamides were synthesized by the methodof Intermediate 9 and used crude, without purification orcharacterization, in the preparation of the example compounds of Table1.

Intermediate 12: 1-[(2,2,2-trifluoroethyl)sulfonyl]piperidin-4-aminetrifluoroacetate

To an ice-bath-cooled solution of 4-(N-Boc-amino)piperidine (300 mg, 1.5mmol) and triethylamine (303 mg, 3 mmol1) in DCM (10 mL) was added2,2,2-trifluoroethanesulfonyl chloride (301 mg, 1.65 mmol), and themixture stirred at room temperature for 2 h. The resulting precipitatewas collected by filtration and dried under vacuum to give tert-butyl{1-[(2,2,2-trifluoroethyl)sulfonyl]piperidin-4-yl}carbamate (12a, 300mg, 58%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=4.47 (q, J=10.2Hz, 2H), 3.63-3.51 (m, 2H), 3.44-3.36 (m, 1H), 3.01-2.83 (m, 2H), 1.80(d, J=10.5 Hz, 2H), 1.47-1.27 (m, 2H), 1.39 (s, 9H).

Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl{1-[(2,2,2-trifluoroethyl)sulfonyl]piperidin-4-yl}carbamate (12a, 300mg, 0.87 mmol) in DCM (10 mL), and the mixture stirred at roomtemperature for 14 h. Volatiles were evaporated and the residue driedunder vacuum to give 1-[(2,2,2-trifluoroethyl)sulfonyl]piperidin-4-amineTFA salt (Intermediate 12, 300 mg, 74%) as a white gum. ¹H NMR (400 MHz,DMSO-d6) δ=8.05 (br s, 3H), 4.65-4.35 (m, 2H), 3.70 (d, J=12.8 Hz, 2H),3.20 (d, J=4.8 Hz, 1H), 2.95 (t, J=11.7 Hz, 2H), 1.98 (d, J=10.5 Hz,2H), 1.66-1.38 (m, 2H).

Intermediate 13: 1-(but-3-yn-1-ylsulfonyl)piperidin-4-amineMethanesulfonate

A solution of but-3-yne-1-sulfonyl chloride (653 mg, 4.3 mmol) in DCM(36 mL) under nitrogen was cooled in an acetone/dry ice bath. Solid4-(N-Boc-amino)piperidine (714 mg, 3.6 mmol) was partially dissolved inDCM (8 mL) and was added via syringe. Triethylamine (646 μL, 4.6 mmol)was added dropwise over 1 minute. The mixture was stirred in the coolingbath under nitrogen for 30 minutes. While still cooled, the reaction wasdiluted with saturated aqueous NaHCO₃ (10 mL) and deionized water (10mL). The mixture was extracted with DCM (50 mL). The organic layer wasdried over sodium sulfate and evaporated to give tert-butyl(1-(but-3-yn-1-ylsulfonyl)piperidin-4-yl)carbamate (13a, 1.08 g, 96%) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ=4.45 (br s, 1H), 3.76 (d,J=12.7 Hz, 2H), 3.66-3.48 (m, 1H), 3.17-3.08 (m, 2H), 3.03-2.88 (m, 2H),2.70 (dt, J=2.7, 7.6 Hz, 2H), 2.17-2.07 (m, 1H), 2.03 (dd, J=2.9, 13.1Hz, 2H), 1.54-1.35 (m, 11H).

To a solution of tert-butyl(1-(but-3-yn-1-ylsulfonyl)piperidin-4-yl)carbamate (13a, 253 mg, 0.8mmol) in DCM (8 mL) was added methanesulfonic acid (318 μL, 4.8 mmol),and the resulting solution stirred at room temperature for 30 minutes.The volatiles were evaporated and the residue suspended in ethyl ether(15 mL). The ether was decanted and the solid dried under high vacuum atroom temperature to give 1-(but-3-yn-1-ylsulfonyl)piperidin-4-aminemethanesulfonate (Intermediate 13, 248 mg, 99%) as a white solid. ¹H NMR(400 MHz, DMSO-d6) δ=7.90 (br s, 3H), 3.65 (d, J=12.7 Hz, 2H), 3.27 (t,J=7.5 Hz, 2H), 2.93 (t, J=11.4 Hz, 2H), 2.57 (dt, J=2.6, 7.5 Hz, 2H),2.36 (s, 5H), 1.96 (d, J=10.5 Hz, 2H), 1.51 (dq, J=3.9, 12.0 Hz, 2H).MS: 217 [M+H]⁺.

Intermediate 14: (+/−)-cis-3-fluoro-1-(methylsulfonyl)piperidin-4-amine

Racemic cis-(3-fluoro-piperidin-4-yl)-carbamic acid benzyl ester [ArrayBiopharma Inc. Patent: Triazolopyridine Compounds as PIM KinaseInhibitors, WO2010/22081 A1, 2010] was sulfonylated by the method ofIntermediate 12 and deprotected by the method of Intermediate 9 to give(+/−)-cis-3-fluoro-1-(methylsulfonyl)piperidin-4-amine (Intermediate 14)as a light yellow solid. ¹H NMR (400 MHz, CD₃OD) δ=ppm 4.66 (d, J=48.4Hz, 1H), 4.01-3.94 (m, 1H), 3.78-3.74 (m, 1H), 3.00 (dd, J=36.9, 14.0Hz, 1H), 2.98-2.91 (m, 1H), 2.88 (s, 3H), 2.82 (t, J=8 Hz, 1H),1.79-1.73 (m, 2H). MS: 197 [M+H]⁺.

Other alkyl- and aryl-substituted sulfonylpiperidin-4-amines weresynthesized by the methods of Intermediate 9, Intermediate 12, orIntermediate 13 and used crude, without purification orcharacterization, in the preparation of the example compounds on Table1.

Intermediate 15: (±)-(1R*,2R*)-2-amino-1-ethylcyclopentan-1-ol

Epoxidation of 1-ethylcyclopentene (CAS #2146-38-5) followed by ringopening and Cbz-deprotection by the method of Intermediate 1 afforded(±)-(1R*,2R*)-2-amino-1-ethylcyclopentan-1-ol (Intermediate 15) as ayellow gum. ¹H NMR (400 MHz, DMSO-d6) δ=2.86 (dd, J=3.5, 6.3 Hz, 1H),2.03-1.92 (m, 1H), 1.63-1.51 (m, 4H), 1.41-1.35 (m, 2H), 1.20 (ddd,J=3.9, 7.2, 13.1 Hz, 1H), 0.87 (t, J=7.5 Hz, 3H).

Intermediate 15 was further elaborated by the method of Intermediate 2and Method A to make Examples 194 and 195, as shown in Table 1.

Intermediate 16:(±)-(1R*,2S*,4R*)-4-((tert-butyldiphenylsilyl)oxy)-2-methylcyclopentan-1-amine

To a solution of ethyl 2-methyl-4-oxocyclopent-2-ene-1-carboxylate[Dolby, L. J. et al. J. Org. Chem. 1968, 33(12), 4508] (24.0 g, 119mmol) in EtOAc (500 mL) was added 10 wt % Pd/C (6.0 g). Hydrogen gas wasbubbled through the mixture for about 5 minutes, then the mixture wasstirred under 30 psi hydrogen for 48 h. The hydrogen source was removedand the mixture was purged with nitrogen for 5 minutes. The Pd/C wasfiltered off using a pad of Celite®, which was washed with ethylacetate. The filtrate was concentrated to afford 24 g yellow oil. Thecrude oil was purified via silica gel chromatography (eluting withpetroleum ether/EtOAc 10/1 to 3/1) to give (±)-ethyl(1R*,2S*)-2-methyl-4-oxocyclopentane-1-carboxylate (16a, 19.3 g, 80%) asan oil. ¹H NMR (400 MHz, CDCl₃) δ=4.16-4.09 (m, 2H), 3.15-3.08 (m, 1H),2.63 (td, J=7.4, 14.6 Hz, 1H), 2.58-2.49 (m, 1H), 2.36-2.24 (m, 2H),2.13-2.04 (m, 1H), 1.22 (t, J=7.2 Hz, 3H), 1.00 (d, J=7.0 Hz, 3H).

A solution of (±)-ethyl(1R*,2S*)-2-methyl-4-oxocyclopentane-1-carboxylate (16a, 10 g, 59 mmol)in ethanol (300 mL) was chilled to 0° C. under nitrogen. Sodiumborohydride (1.11 g, 29.4 mmol) was added in small portions. Thereaction was allowed to stir at 0° C. for 1 hour. The reaction wasquenched by the slow addition of sat. aq. ammonium chloride solution (50mL), followed by water (50 mL) to dissolve any solids. Ethanol wasremoved under reduced pressure and the aqueous residue extracted withMTBE (2×300 mL). The combined organics were washed with sat. aq. NaCl(500 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to give (±)-ethyl(1R*,2S*,4R*)-4-hydroxy-2-methylcyclopentane-1-carboxylate (16b, 9.9 g,97%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ=4.24-4.16 (m, 1H),4.14-4.03 (m, 2H), 3.57 (br s, 1H), 2.74 (dt, J=3.8, 7.4 Hz, 1H),2.29-2.11 (m, 2H), 2.04-1.95 (m, 1H), 1.89 (td, J=3.6, 14.2 Hz, 1H),1.35-1.26 (m, 1H), 1.23-1.18 (m, 3H), 0.95 (d, J=6.8 Hz, 3H).

A mixture of (±)-ethyl(1R*,2S*,4R*)-4-hydroxy-2-methylcyclopentane-1-carboxylate (16b, 9.9 g,57 mmol) in aqueous NaOH (115 mL of 1 M, 115 mmol) was stirred at roomtemperature for 18 h. MTBE (100 mL) was added and the layers separated.The aqueous layer was cooled to 0° C. and acidified to pH 1 by slowaddition of aqueous HCl (5N). The aqueous suspension was extracted withEtOAc (4×200 mL). The combined organic layers were washed with sat. aq.NaCl (100 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated to give(±)-(1R*,2S*,4R*)-4-hydroxy-2-methylcyclopentane-1-carboxylic acid (16c,7.9 g, 95%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ=12.01 (br s,1H), 4.67 (br s, 1H), 4.02 (t, J=6.9 Hz, 1H), 2.67 (q, J=7.9 Hz, 1H),2.19 (td, J=7.1, 14.1 Hz, 1H), 2.03-1.93 (m, 2H), 1.81-1.67 (m, 1H),1.28-1.15 (m, 1H), 0.93 (d, J=6.3 Hz, 3H).

A solution of(±)-(1R*,2S*,4R*)-4-hydroxy-2-methylcyclopentane-1-carboxylic acid (16c,7.9 g, 55 mmol), tert-butyl(chloro)diphenylsilane (TBDPSCI, 15.8 g, 57.5mmol), and DBU (10 g, 66 mmol) in acetonitrile (200 mL) was stirred atroom temperature for 15 h. The reaction mixture was concentrated andpartitioned between DCM and sat. aq. ammonium chloride. The organiclayer was washed with sat. aq. NaCl over sodium sulfate, concentrated,and purified by silica gel chromatography (eluting with 100% DCM toDCM/MeOH 20/1) to give(±)-(1R*,2S*,4R*)-4-((tert-butyldiphenylsilyl)oxy)-2-methylcyclopentane-1-carboxylicacid (18 g, 85%) as an impure yellow oil which was used in the next stepwithout further purification.

To a solution of(±)-(1R*,2S*,4R*)-4-((tert-butyldiphenylsilyl)oxy)-2-methylcyclopentane-1-carboxylicacid (700 mg, 1.83 mmol), sodium azide (297 mg, 4.57 mmol),tetrabutylammonium bromide (TBAB, 118 mg, 0.366 mmol), and zinc triflate(200 mg, 0.549 mmol) in THE (20 mL) was added di-tert-butyl dicarbonate(599 mg, 2.74 mmol). The mixture was stirred in a sealed tube underargon at 60° C. for 24 h, then tert-butanol (67.8 mg, 0.915 mmol) wasadded via syringe. Stirring was continues at 60° C. for another 24 h.The mixture was cooled to room temperature and quenched with 10% aqueousNaNO₂ (10 mL). Ethyl acetate was added and the biphasic mixture stirredfor 30 min at room temperature. The two layers were separated, and theorganic layer was washed successively with sat. aq. NH₄Cl (15 mL), andbrine (15 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated to give crude 16d as yellow oil. A total ofseven individual batches were run separately on 700 mg scale asdescribed above, then the batches were combined and purified via silicagel chromatography (petroleum ether/EtOAc 10/1) to give (±)-tert-butyl((1R*,2S*,4R*)-4-((tert-butyldiphenylsilyl)oxy)-2-methylcyclopentyl)carbamate(16d, 3.3 g, 56% from a total of seven batches of 700 mg each). MS:476.1 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ=7.62-7.57 (m, 4H), 7.48-7.40(m, 6H), 6.59 (d, J=8.8 Hz, 1H), 4.13 (t, J=6.1 Hz, 1H), 3.77-3.61 (m,1H), 1.99-1.82 (m, 3H), 1.66 (td, J=6.6, 12.9 Hz, 1H), 1.37 (s, 10H),1.00 (s, 9H), 0.88 (d, J=6.5 Hz, 3H). 2D NMR analysis confirmed therelative stereochemical assignment of all cis.

Trifluoroacetic acid (10 mL) was added to a solution of (±)-tert-butyl((1R*,2S*,4R*)-4-((tert-butyldiphenylsilyl)oxy)-2-methylcyclopentyl)carbamate(16d, 1.9 g, 4.2 mmol) in DCM (30 mL), and the solution was stirred atroom temperature for 2 h. The reaction solution was concentrated, theresidue diluted with DCM (100 mL), and sat. aq. NaHCO₃ (50 mL) was addedto neutralize residual acid. The layers were separated and aqueous layerextracted with DCM (100 mL). The combined organic layers were dried,filtered and concentrated to give the crude(±)-(1R*,2S*,4R*)-4-((tert-butyldiphenylsilyl)oxy)-2-methylcyclopentan-1-amine(Intermediate 16, 1.5 g) as an oil. ¹H NMR (400 MHz, CDCl₃) δ=7.72 (dd,J=1.8, 7.8 Hz, 1H), 7.66 (ddd, J=1.5, 3.5, 7.8 Hz, 3H), 7.48-7.32 (m,6H), 4.30-4.19 (m, 1H), 3.08 (d, J=4.3 Hz, 1H), 2.03-1.90 (m, 2H), 1.79(br s, 1H), 1.68 (td, J=3.2, 13.9 Hz, 1H), 1.51-1.39 (m, 1H), 1.13-0.95(m, 12H).

Intermediate 16 was further elaborated using the method of Intermediate5, via S_(N)Ar addition to ethyl4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate, reduction of theester by LAH, and oxidation of the resulting alcohol by MnO₂. Thetert-butyldiphenylsilyl protecting group was incidentally cleaved duringLAH reduction. Subsequent synthesis following Method A produced Examples199 and 200, as shown in Table 1.

Intermediate 17)-(1R*,3S*,4S*)-3-amino-4-fluorocyclohexan-1-olhydrochloride

In a sealed polypropylene vessel a solution of (±)-(tert-butyl (1S*,3R*,6R*)-3-(benzyloxy)-7-azabicyclo[4.1.0]heptane-7-carboxylate[Crotti, P. et al. J. Org. Chem. 1995, 60, 2514] (4.0 g, 13 mmol) andtriethylamine trihydrofluoride (12.8 g, 79.2 mmol) in acetonitrile (10mL) was stirred at 90° C. for 18 h. After cooling to room temperature,the mixture was partitioned between water and ethyl acetate. The organiclayer was washed with sat. aq. NaCl, dried over sodium sulfate,concentrated, and purified by silica gel chromatography (eluting withpetroleum ether/EtOAc 10/1 to 1/1) to afford 2.4 g of the desiredproduct but with 85% purity by HPLC. This material was further purifiedby preparative HPLC to afford (±)-tert-butyl ((1S*,2S*,5R*)-5-(benzyloxy)-2-fluorocyclohexyl)carbamate (17a, 1.88 g,44%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ=7.47-7.18 (m, 5H),4.62-4.48 (m, 2H), 4.40-4.18 (m, 1H), 3.92 (br dd, J=3.9, 10.7 Hz, 1H),3.78-3.68 (m, 1H), 2.16 (br dd, J=1.8, 11.0 Hz, 1H), 2.04-1.84 (m, 3H),1.57-1.39 (m, 11H).

A solution of (±)-tert-butyl ((1S*,2S*,5R*)-5-(benzyloxy)-2-fluorocyclohexyl)carbamate (17a, 1.88 g,5.81 mmol) and Pd(OH)₂/C (1.0 g) in methanol (100 mL) was stirred under45 psi hydrogen at room temperature for 18 h. The catalyst was filteredoff and the filtrate concentrated to afford (±)-tert-butyl ((1S*,2S*,5R*)-2-fluoro-5-hydroxycyclohexyl)carbamate (17b, 1.36 g, 100%)as white solid which was used without further purification. ¹H NMR (400MHz, CD₃OD) δ=4.42-4.15 (m, 1H), 4.04-3.86 (m, 2H), 3.33 (td, J=1.6, 3.3Hz, 1H), 2.00-1.82 (m, 3H), 1.81-1.71 (m, 1H), 1.62-1.50 (m, 2H), 1.46(s, 9H).

To a solution of (±)-tert-butyl ((1S*,2S*,5R*)-2-fluoro-5-hydroxycyclohexyl)carbamate (17b, 1.36 g, 5.83mmol) in MeOH (20 mL) was added 4 M HCl in MeOH (20 mL, 80 mmol). Themixture was stirred at room temperature for 1 hour, then concentratedand lyophilized to give(±)-(1R*,3S*,4S*)-3-amino-4-fluorocyclohexan-1-ol hydrochloride(Intermediate 17, 0.985 g, 100%) as a white hygroscopic solid. MS: 134.1[M+H]⁺, ¹H NMR (400 MHz, D₂O) δ=4.75-4.52 (m, 1H), 4.23-4.09 (m, 1H),3.69-3.53 (m, 1H), 2.22-2.03 (m, 2H), 1.95-1.80 (m, 2H), 1.75-1.61 (m,2H), ¹⁹F NMR (376 MHz, D₂O) δ=−179.8 (s, 1F).

Intermediate 17 was used without further purification as described forIntermediate 3 and Method A to afford Examples 217-220 shown in Table 1.

Intermediate 18: (1S,2S,5R)-5-((tert-butyldiphenylsilyl)oxy)-2-methylcyclohexan-1-amine

A solution of ethyl (1S,2S,5R)-5-hydroxy-2-methylcyclohexane-1-carboxylate [Raw, A. S. andJang, E. B. Tetrahedron 2000, 56, 3285-3290] (6.25 g, 33.6 mmol),imidazole (6.85 g, 101 mmol), and tert-butyl(chloro)diphenylsilane (18.4g, 67.1 mmol) in DMF (80 mL) was stirred at 20° C. for 40 h. Thereaction was quenched with deionized water (200 mL) and extracted withethyl acetate (3×80 mL). The combined organics were washed with sat. aq.NaCl, dried over sodium sulfate, concentrated, and purified by silicagel chromatography (eluting with ethyl acetate in pet. ether) to giveethyl (1S,2S,5R)-5-((tert-butyldimethylsilyl)oxy)-2-methylcyclohexane-1-carboxylate(18a, 10.5 g, 74%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃)δ=7.72-7.62 (m, 4H), 7.47-7.35 (m, 6H), 4.21-4.02 (m, 3H), 2.67-2.50 (m,1H), 1.87-1.77 (m, 1H), 1.69-1.58 (m, 3H), 1.52-1.32 (m, 3H), 1.26 (t,J=7.2 Hz, 3H), 1.10-1.07 (m, 9H), 0.95 (d, J=6.0 Hz, 3H).

A mixture of sodium hydroxide (4.71 g, 118 mmol) and(1S,2S,5R)-5-((tert-butyldimethylsilyl)oxy)-2-methylcyclohexane-1-carboxylate(18a, 5.0 g, 11.8 mmol) in ethanol (80 mL) and deionized water (80 mL)was stirred at 80° C. for 15 h. The volatiles were evaporated and theaqueous residue neutralized to pH 6 with 1 N HCl. The product wasextracted with ethyl acetate (3×100 mL). The combined organics werewashed with sat. aq. NaCl, dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (eluting with ethyl acetate inpet. ether) to give (1S,2S,5R)-5-((tert-butyldimethylsilyl)oxy)-2-methylcyclohexane-1-carboxylicacid (18b, 2.55 g, 55%) as a light grey solid. Chiral SFC showed noepimerization. [Major peak at rt 2.72 min, Chiral SFC method: Column:ChiralCel OJ-H 150×4.6 mm I.D., 5 μm. Mobile phase: A: CO₂ B: ethanol(0.05% DEA). Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3min, then 5% of B for 1.5 min. Flow rate: 2.5 mL/min Column temperatureat 40° C.].

A solution of (1S,2S,5R)-5-((tert-butyldimethylsilyl)oxy)-2-methylcyclohexane-1-carboxylicacid (18b, 4.0 g, 10.1 mmol), triethylamine (3.1 g, 30.3 mmol), anddiphenyl phosphoryl azide (DPPA, 4.2 g, 15.1 mmol) in toluene (100 mL)was stirred at 110° C. for 3 h. Benzyl alcohol (5.5 g, 50.4 mmol) wasadded and stirring continued at 110° C. for 32 h more. After cooling toroom temperature, the reaction was concentrated and the residue waspurified by silica gel chromatography (eluting with ethyl acetate inpet. ether) to give benzyl ((1S,2S,5R)-5-((tert-butyldiphenylsilyl)oxy)-2-methylcyclohexyl)carbamate(18c, 2.8 g, 55%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ=7.79-7.62 (m,4H), 7.48-7.31 (m, 11H), 5.26-5.07 (m, 2H), 4.49-4.37 (m, 1H), 4.18-4.05(m, 1H), 3.92-3.71 (m, 1H), 2.11-1.92 (m, 1H), 1.78-1.60 (m, 3H),1.35-1.19 (m, 3H), 1.14-1.01 (m, 12H). MS; 524 [M+Na]⁺.

Benzyl ((1S,2S,5R)-5-((tert-butyldiphenylsilyl)oxy)-2-methylcyclohexyl)carbamate(18c, 3.50 g, 6.98 mmol) in methanol (75 mL) was treated with 10%palladium on carbon (350 mg) and stirred at 30° C. under a hydrogenballoon for 16 h. The catalyst was removed by filtration and thefiltrate was evaporated to give (1S,2S,5R)-5-((tert-butyldiphenylsilyl)oxy)-2-methylcyclohexan-1-amine(Intermediate 18, 2.5 g, 98%) as an oil. ¹HNMR (400 MHz, CDCl₃)δ=7.77-7.61 (m, 4H), 7.47-7.35 (m, 6H), 4.26-4.09 (m, 1H), 2.95-2.77 (m,1H), 1.91-1.83 (m, 1H), 1.67-1.58 (m, 3H), 1.53-1.43 (m, 1H), 1.35-1.23(m, 1H), 1.20-1.12 (m, 2H), 1.09 (s, 12H). MS: 368 [M+H]⁺.

Intermediate 18 was employed in synthesis using the methods ofIntermediate 3 and Method A, with silyl deprotection by TBAF as anadditional step before thioether oxidation with OXONE®, to produceExample 216, as shown in Table 1.

Intermediate 19:(±)-(3S*,4R*)-4-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-3-methyltetrahydrofuran-3-ol

By the method of Intermediate 5, S_(N)Ar addition of ethyl4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate (CAS #5909-24-0)(6.0 g, 26 mmol), and (±)-(3S*,4R*)-4-amino-3-methyltetrahydrofuran-3-olhydrochloride [Eli Lilly and Co. Patent: Selective Androgen ReceptorModulators. WO 2013/055577 A1, 2013] (6.1 g, 28 mmol) withdiisopropylethyl amine (20 g, 155 mmol) in ethanol (120 mL) afforded(±)-ethyl4-(((3R*,4S*)-4-hydroxy-4-methyltetrahydrofuran-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate(19a, 6.2 g, 77%), which was then reduced by LAH (1.91 g, 50.5 mmol) inTHE (150 mL). After aqueous workup, the major isomer was isolated bypreparative HPLC, to give(±)-(3S*,4R*)-4-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-3-methyltetrahydrofuran-3-ol(Intermediate 19, 1.51 g, 33%) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ=7.80 (s, 1H), 6.08 (d, J=6.0 Hz, 1H), 4.65-4.56 (m, 3H), 4.36 (dd,J=9.16, 7.65 Hz, 1H), 3.90 (d, J=9.0 Hz, 1H), 3.76 (d, J=9.3 Hz, 1H),3.65 (dd, J=9.16, 6.90 Hz, 1H), 2.54-2.49 (m, 3H), 1.26 (s, 3H).

Intermediate 19 was oxidized to the corresponding aldehyde using MnO₂ bythe method of Intermediate 5, and further elaborated by Method A tosynthesize Examples 197 and 198 and Example 198, as shown in Table 1.

Intermediate 20:(±)-(1R*,2S*,3R*)-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclopentan-1-olIntermediate 21:(±)-(1R*,2R*,3S*)-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclopentan-1-olIntermediate 22:(±)-(1R*,2R*,3R*)-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclopentan-1-ol

A suspension of N-(2-methyl-3-oxocyclopent-1-en-1-yl)acetamide [Huang,K.; Guan, Z.-H.; Zhang, X., Tet. Lett., 2014, 55, 1686-1688] (17.6 g,115 mmol), 20% Pd(OH)₂ (wet) (4.4 g, 28.8 mmol), and DIPEA (37.2 g, 288mmol) in ethyl acetate (80 mL) was hydrogenated in a stainless steelreactor at 20 Bar and 80° C. for 18 h. The catalyst was removed byfiltration through a bed of Celite®, and the filter cake washed withethyl acetate (100 mL) and water (100 mL). The biphasic filtrate layerswere separated, and the aqueous layer extracted with ethyl acetate (3×30mL). The combined organics were dried over sodium sulfate andconcentrated to give a mixture of diastereomers ofN-(3-hydroxy-2-methylcyclopentyl)acetamide (20a, 2.32 g), as a yellowoil. A different mixture of 20a diastereomers remained in the aqueouslayer, which were not isolated but carried on in solution. Bothfractions were taken to the next step without further purification.

Solid potassium hydroxide (8.21 g, 146 mmol) was added portion wise to asolution of N-(3-hydroxy-2-methylcyclopentyl)acetamide (20a, 2.30 g,from the organic extracts above) in water (100 mL). The mixture washeated to 90° C. for 72 h. After cooling the solution to roomtemperature, di-tert-butyl-dicarbonate (6.39 g, 29.3 mmol) andtetrahydrofuran (150.0 mL) were added. The reaction was stirred at roomtemperature for 48 h. After aqueous work-up the products were purifiedby silica gel chromatography (eluting with 0-80% ethyl acetate/heptane)to give tert-butyl (3-hydroxy-2-methylcyclopentyl)carbamate (20b, 3.15g) as a mixture of diastereomers. The aqueous layer from the first step,containing a different mixture of 20a diastereomers, was hydrolyzed andBoc-protected by the same procedure to give a second batch of 20b (10.1g, mixture of diastereomers).

A solution of tert-butyl (3-hydroxy-2-methylcyclopentyl)carbamate (20b,9.3 g, 43.2 mmol) in 1,4-dioxane (50 mL) was treated with hydrochloricacid (216 mL of a 4M solution in 1,4-dioxane, 864 mmol), and stirred atroom temperature for 2 h. The volatiles were evaporated, leaving crude3-amino-2-methylcyclopentan-1-ol hydrochloride (20c, 7.0 g) as a mixtureof diastereomers, which was used in the subsequent reaction withoutfurther purification. The other batches of 20b were treated similarly toobtain batches of 20c with different mixtures of diastereomers.

A solution of crude 3-amino-2-methylcyclopentan-1-ol hydrochloride (20c,7.0 g, 60.78 mmol, mixture of diastereomers), diisopropylethyl amine(39.3 g, 304 mmol), [4-chloro-2-(methylsulfanyl)pyrimidin-5-yl]methanol(CAS #1044145-59-6) (11.6 g, 60.8 mmol) in DMSO (20 mL) was heated to50° C. for 48 h. Triethylamine (18.5 g, 182 mmol) was added, and heatingcontinued for 20 h more. The reaction mixture was poured into ice/waterand extracted with ethyl acetate (3×100 mL). The combined organics werewashed with saturated aqueous NaCl (3×100 mL), washed with deionizedwater (100 mL), dried over sodium sulfate and concentrated to give3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclopentan-1-olas a mixture of diastereomers. The other batches of 20c were treatedsimilarly to obtain different mixtures of diastereomers.

The various mixtures of3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclopentan-1-oldiastereomers were resolved into four separate racemic pairs overseveral steps by crystallization, flash chromatography, and non-chiralpreparative HPLC. Stereochemistry of the resulting enantiomeric pairswas determined by 2-D NMR.

(±)-(1R*,2S*,3R*)-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclopentan-1-ol(Intermediate 20): ¹H NMR (400 MHz, DMSO-d₆) δ=7.81 (s, 1H), 6.46 (d,J=7.8 Hz, 1H), 5.10 (t, J=5.5 Hz, 1H), 4.43 (d, J=4.2 Hz, 1H), 4.33 (d,J=5.5 Hz, 2H), 4.24 (quin, J=8.5 Hz, 1H), 3.99 (d, J=3.0 Hz, 1H), 2.42(s, 3H), 2.12-2.23 (m, 1H), 1.87-2.00 (m, 1H), 1.75-1.87 (m, 1H),1.46-1.59 (m, 1H), 1.27-1.41 (m, 1H), 0.94 (d, J=6.8 Hz, 3H). MS: 270[M+H]⁺.

(±)-(1R*,2R*,3S*)-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclopentan-1-ol(Intermediate 21): ¹H NMR (400 MHz, DMSO-d₆) δ=7.81 (s, 1H), 6.57 (d,J=7.8 Hz, 1H), 5.11 (t, J=5.5 Hz, 1H), 4.73 (d, J=4.6 Hz, 1H), 4.32 (d,J=5.5 Hz, 2H), 3.86-4.13 (m, 1H), 3.48-3.69 (m, 1H), 2.40 (s, 3H),1.93-2.08 (m, 1H), 1.79-1.93 (m, 1H), 1.65-1.79 (m, 1H), 1.44-1.62 (m,2H), 0.98 (d, J=6.8 Hz, 3H). MS: 270 [M+H]⁺.

(±)-(1R*,2R*,3R*)-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclopentan-1-ol(Intermediate 22): ¹H NMR (400 MHz, DMSO-d6) δ=7.81 (s, 1H), 6.34 (d,J=7.9 Hz, 1H), 5.21 (t, J=5.4 Hz, 1H), 4.57-4.70 (m, 2H), 4.25-4.41 (m,2H), 3.74 (quin, J=5.1 Hz, 1H), 2.34-2.46 (m, 3H), 2.00-2.12 (m, 2H),1.89-2.00 (m, 1H), 1.49-1.63 (m, 1H), 1.31-1.47 (m, 1H), 0.74 (d, J=7.2Hz, 3H). MS: 270 [M+H]⁺.

The fourth of the four possible pairs of enantiomers was also isolated,but not used in further synthesis.(±)-(1R*,2S*,3S*)-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclopentan-1-ol:¹H NMR (400 MHz, DMSO-d6) δ=7.78 (s, 1H), 6.64 (d, J=8.7 Hz, 1H), 5.13(t, J=5.2 Hz, 1H), 4.75 (d, J=3.4 Hz, 1H), 4.44-4.62 (m, 1H), 4.30 (s,2H), 3.89-4.05 (m, 1H), 2.41 (s, 3H), 1.91-2.04 (m, 2H), 1.73-1.81 (m,1H), 1.54-1.73 (m, 2H), 0.89 (d, J=7.1 Hz, 3H). MS: 270 [M+H]⁺.

Intermediate 20, Intermediate 21, and Intermediate 22 were separatelyoxidized to the corresponding aldehydes by MnO2 using the method ofIntermediate 1, and further elaborated by Method A and other generalsynthetic methods described herein to synthesize Examples 201-210 shownin Table 1.

Intermediate 23: (±)-(1S*,2R*,3S*)-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol

A solution of N-(2-methyl-3-oxocyclohex-1-en-1-yl)acetamide [CAS#36887-93-1](20 g, 120 mmol), DIPEA (38.8 g, 300 mmol) and 20% Pd/C (2g, 12 mmol) in ethyl acetate (80 mL) was hydrogenated in a stainlesssteel vessel under 20 bar hydrogen at 80° C. for 20 h. The reactionmixture was filtered while still hot, and the filter cake washed withhot ethyl acetate. The combined filtrate was concentrated and the solidresidue crystallized in DCM/heptane to give a mixture of diastereomersof N-(3-hydroxy-2-methylcyclohexyl)acetamide (23a, 10.0 g, 51%) as awhite solid.

Solid potassium hydroxide (22.9 g, 409 mmol) was added portion wise to asolution of N-(3-hydroxy-2-methylcyclohexyl)acetamide (23a, 7.0 g, 40mmol) in water (200.0 mL). The reaction was heated to 100° C. for 24 hand then to 90° C. for 72 h more. The solution was cooled to roomtemperature and di-tert-butyl dicarbonate (9.8 g, 45.0 mmol) andtetrahydrofuran (150 mL) were added. Stirring was continued at roomtemperature for 48 h. The solution was extracted with ethyl acetate(3×100 mL) and the organics were combined, dried over sodium sulfate andconcentrated. The residue was purified by silica gel chromatography(eluting with 0-100% ethyl acetate in heptane) to give tert-butyl(3-hydroxy-2-methylcyclohexyl)carbamate (23b, 2.50 g, 30%) as adiastereomeric mixture. ¹H NMR (400 MHz, CDCl₃) δ=4.20-4.60 (m, 1H),3.84-4.04 (m, 1H), 3.44-3.66 (m, 1H), 1.89-2.02 (m, 1H), 1.67-1.88 (m,2H), 1.49-1.58 (m, 1H), 1.45 (s, 9H), 1.14-1.42 (m, 2H), 0.95-1.12 (m,3H).

A solution of tert-butyl (3-hydroxy-2-methylcyclohexyl)carbamate (23b,2.50 g, 10.9 mmol) in 1,4-dioxane (100 mL) was treated with hydrochloricacid (40.9 mL of a 4M solution in 1,4-dioxane, 164 mmol), and stirred atroom temperature for 20 h. The volatiles were removed and the residuedried in a vacuum oven for 72 h to give a mixture of diastereomers of3-amino-2-methylcyclohexan-1-ol hydrochloride (23c, 1.68 g, 93%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d6) δ=7.57-8.28 (m, 3H), 3.58-3.78(m, 1H), 2.55-3.19 (m, 1H), 1.71-2.01 (m, 1H), 1.60-1.71 (m, 1H),1.51-1.60 (m, 2H), 1.06-1.51 (m, 3H), 0.70-1.06 (m, 3H).

A solution of [4-chloro-2-(methylsulfanyl)pyrimidin-5-yl]methanol (CAS#1044145-59-6) (2 g, 10.5 mmol), 3-amino-2-methylcyclohexan-1-olhydrochloride (23c 1.5 g, 11.7 mmol, mixture of diastereomers) and DIPEA(4.5 g, 35.1 mmol) in DMSO (20.0 mL) was heated to 50° C. for 20 h, thenpoured over ice/water and extracted with ethyl acetate (3×100 mL). Theorganics were washed with sat. aq. NaCl (3×50 mL), dried over sodiumsulfate, concentrated, and purified by silica gel chromatography,eluting with 0-100% ethyl acetate in heptane. This method was adequateto separate the desired diastereomer, (±)-(1S*,2R*,3S*)-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol(Intermediate 23, 169 mg, 5.7%, the least polar of the product peaks) asa white solid. The relative stereochemistry was determined by 2-D NMR.¹H NMR (400 MHz, DMSO-d6) δ=7.79 (s, 1H), 6.30 (d, J=8.6 Hz, 1H), 5.12(t, J=5.5 Hz, 1H), 4.36 (d, J=3.9 Hz, 1H), 4.32 (d, J=5.5 Hz, 2H),4.05-4.17 (m, 1H), 3.77 (br s, 1H), 2.41 (s, 3H), 1.78-1.94 (m, 1H),1.68-1.75 (m, 1H), 1.54-1.65 (m, 1H), 1.33-1.50 (m, 2H), 1.11-1.29 (m,2H), 0.89 (d, J=6.8 Hz, 3H). MS: 284 [M+H]⁺.

Intermediate 23 was oxidized to the corresponding aldehyde with MnO₂,then further elaborated by Method A to make Examples 221 and 222 shownin Table 1.

EXAMPLES General Methods and Representative Examples Method A (AldolCyclization) Example 1:8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of4-(cyclopentylamino)-2-(methylsulfanyl)pyrimidine-5-carbaldehyde[VanderWel, et al. J. Med. Chem. 2005, 48, 2371] (2.0 g, 8.4 mmol) inanhydrous THE (50 mL) was added EtOAc (2.23 g, 25.3 mmol) at −70° C. Themixture was stirred at this temperature for 15 min, then LHMDS (1.0 M inTHF, 29.5 mmol, 29.5 mL) was added dropwise. The reaction was stirred at−70° C. for 30 min and then at 20° C. for 16 h. The solution was cooledin an ice bath, quenched with water, and then extracted with EtOAc (50mL×3). The combined organic layers were washed with aq NH₄Cl (30 mL),and sat. aq NaCl (30 mL), dried over sodium sulfate, and concentrated.The residue was purified by silica gel chromatography (eluting withpetroleum ether/EtOAc 10/1 to 3/1) to give8-cyclopentyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1A,2.01 g, 91%) as a white solid. MS: 262 [M+H]⁺.

OXONE®, (23.5 g, 38.3 mmol) was added to a cooled (0° C.) solution of8-cyclopentyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1A,5.0 g, 19.13 mmol) in THE (100 mL) and water (20 mL), and the mixturestirred at room temperature for 2 h. The mixture was diluted with EtOAc(300 mL), washed with water (100 mL), dried over sodium sulfate, andconcentrated to give crude8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1B,5.40 g, 96%) as a gray solid. MS: 315 [M+Na]⁺.

A solution of crude8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1B,5.40 g, 17.0 mmol), 4-amino-1-methanesulfonylpiperidine (CAS#402927-97-3, 5.34 g, 24.9 mmol) and DIPEA (14.7 mL, 82.8 mmol) in DMSO(70 mL) was stirred at 65° C. for 18 h. The reaction mixture was dilutedwith DCM (150 mL), washed with aq NH₄Cl (80 mL×2), dried over sodiumsulfate, and concentrated to dryness. The crude product wasrecrystallized with 1/2 EtOAc:petroleum ether (50 mL) to give8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 1, 4.65 g, 72%) as a gray solid. ¹H NMR (400 MHz, DMSO-d6)δ=8.68-8.54 (m, 1H), 7.88 (d, J=6.3 Hz, 1H), 7.68 (d, J=9.3 Hz, 1H),6.28-6.16 (m, 1H), 5.92-5.74 (m, 1H), 4.02-3.82 (m, 1H), 3.58 (d, J=10.8Hz, 2H), 2.96-2.82 (m, 5H), 2.33 (d, J=1.8 Hz, 1H), 2.19 (br s, 1H),2.03-1.91 (m, 4H), 1.78-1.55 (m, 6H). MS: 392 [M+H]⁺.

Example 2:8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

To a 2 L three-necked flask equipped with a mechanical stirrer and aninternal thermometer was added solid4-{[(1R,2R)-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 2, 34.2 g, 128 mmol), THE (400 mL), and EtOAc (33.4 mL,333 mmol). The solution was purged with nitrogen and cooled in aMeOH-ice bath to −5° C. internal. Via cannula, LHMDS (1.0 M solution inTHF, 4×100 mL freshly opened bottles, 400 mmol) was added, slowly enoughto keep the internal temperature at −5° C. A light yellow precipitatebegan to form after ˜300 mL LHMDS solution had been added. Stirring wascontinued as the mixture was allowed to gradually warm to roomtemperature overnight. The resulting red solution was cooled in anice-water bath to ˜3° C. internal, then EtOH (224 mL, 3840 mmol) wasadded via cannula, slowly enough to keep the internal temp at ˜3° C.internal. The mixture was stirred in the ice bath for 1 hour, then thecooling bath was removed, the solution allowed to warm to 20° C.internal, and stirring continued for 1 h. The solvents were evaporated,the residue diluted with water (180 mL) and sat. aq NaCl (180 mL), andthe aqueous layer extracted with EtOAc (700 mL, then 600 mL×2). Thecombined organic extracts were dried over sodium sulfate andconcentrated to a light yellow-brown foam (43.8 g). This foam wasdissolved in EtOAc (70 mL) and sonicated to induce precipitation. Theresulting solid was collected by filtration, rinsed with EtOAc (10 mL),and dried to give8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(2A, 21.4 g, 58%, >99% ee) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ=8.61 (s, 1H), 7.56 (d, J=9.4 Hz, 1H), 6.60 (d, J=9.4 Hz, 1H), 5.84 (t,J=8.6 Hz, 1H), 2.92-2.76 (m, 1H), 2.64 (s, 3H), 2.34-2.19 (m, 2H),2.13-2.01 (m, 2H), 2.00-1.81 (m, 2H), 1.16 (s, 3H). MS: 292 [M+H]⁺.Optical rotation: [α]_(D) ²²=−12.9 (c 1.0, MeOH). Chiral purity: >99%ee. Chiral SFC/MS analysis was performed on a Chiralpak AD-3, 4.6×100mm, 3 μm column heated to 25° C. and eluted with a mobile phase of CO₂and 40% methanol flowing at 4.0 mL/min and maintained at 120 bar outletpressure. The product peak had a retention time of 0.85 min.

The mother liquor from the above precipitation was evaporated todryness. The residue (24.5 g) was dissolved in EtOAc (30 mL) and thesolution sonicated to induce precipitation. After filtration and drying,a second crop of8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(2A, 4.70 g, 13%, >99% ee) was obtained as a white solid. The totalyield for both crops was 26.1 g (71% at >99% ee) after crystallization.

A solution of8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfanyl)-pyrido[2,3-d]pyrimidin-7(8H)-one(2A, >99% ee, 2.33 g, 8 mmol), 2-MeTHF (40 mL), water (8 mL) and OXONE®(12.3 g, 20 mmol) was stirred at room temperature for 4 h. The solutionwas cooled in a water bath, diluted with water (10 mL) and sat. aq NaCl(10 mL), and extracted with EtOAc (80 mL×3). The combined organicextracts were dried over sodium sulfate, evaporated to a dark oil (3.76g), and purified by silica gel chromatography (eluting with a gradientof 20-100% EtOAc in heptane) to give8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(2B, 2.2 g, 84%) as a foamy solid. ¹H NMR (400 MHz, CDCl₃) δ=8.96 (s,1H), 7.74 (d, J=9.5 Hz, 1H), 6.90 (d, J=9.4 Hz, 1H), 5.77 (t, J=8.5 Hz,1H), 3.40 (s, 3H), 2.92-2.73 (m, 1H), 2.36-2.25 (m, 1H), 2.19-2.08 (m,2H), 2.03-1.85 (m, 2H), 1.14 (s, 3H). MS: 306 [M−18]⁺.

A solution of8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfonyl)-pyrido[2,3-d]pyrimidin-7(8H)-one(2B, 800 mg, 2.47 mmol), and 4-amino-1-methanesulfonylpiperidine (CAS#402927-97-3, 970 mg, 5.44 mmol) in 2-MeTHF (12.4 mL) was heated in a60° C. oil bath for 24 h. After cooling to room temperature, the mixturewas partitioned between EtOAc (80 mL), water (10 mL) and sat. aq NaHCO₃(10 mL). The aqueous layer was further extracted with EtOAc (60 mL×2).The combined organic extracts were dried over sodium sulfate andevaporated to dryness. The residue (1.23 g) was dissolved in EtOAc (11mL), seed crystals were added, and the solution allowed to stand at roomtemperature overnight. The resulting solid was collected by filtration,rinsed with EtOAc (3 mL) and dried to give8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 2, 680 mg, 63%, >99% ee) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ=8.43 (s, 1H), 7.45 (d, J=9.3 Hz, 1H), 6.36 (d, J=9.4 Hz, 1H),5.73 (t, J=8.4 Hz, 1H), 5.34 (br s, 1H), 4.01 (br s, 1H), 3.88-3.74 (m,2H), 3.01-2.89 (m, 2H), 2.83 (s, 4H), 2.36 (br s, 1H), 2.29-2.14 (m,3H), 2.03 (dt, J=2.9, 6.3 Hz, 2H), 1.98-1.89 (m, 1H), 1.88-1.81 (m, 1H),1.78-1.60 (m, 2H), 1.18 (s, 3H). MS: 422 [M+H]⁺. Optical rotation:[α]_(D) ²²−17.0 (c 1.0, CHCl₃). Chiral purity: >99% ee. Chiral SFC/MSanalysis was performed on a Lux Cellulose-1, 4.6×100 mm, 3 μm columnheated to 25° C. and eluted with a mobile phase of CO₂ and 5-60%methanol gradient in 3.0 min flowing at 4.0 mL/min and maintained at 120bar outlet pressure. The product peak had a retention time of 2.37 min.

The filtrate from the above crystallization was concentrated to dryness,the residue dissolved in EtOAc (50 mL), and the solution washed with aqHCl (0.1 M, 12.4 mL). The organic layer was washed with sat. aq NaHCO₃(20 mL), dried over sodium sulfate, and concentrated, affording a secondbatch of8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 2, 361 mg, 31%, 94% total yield), with NMR and LCMS spectraconsistent with the first crop.

Example 3:8-[(1R,3R)-3-hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one

A solution of LHMDS (1.0 M in THF, 60.7 mL, 60.7 mmol) was addeddropwise to a chilled (−70° C.) solution of EtOAc (3.56 g, 40.4 mmol) inTHE (40 mL). The mixture was stirred at 0° C. for 30 min, then asolution of4-{[(1R,3R)-3-hydroxycyclohexyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 3, 2.70 g, 10.1 mmol) in THE (10 mL) was added dropwise.When addition was complete, stirring was continued at room temperaturefor 18 h. The solution was quenched with water (40 mL) and extractedwith EtOAc (40 mL×3). The combined organic extracts were dried oversodium sulfate, concentrated, and the residue purified by silica gelchromatography (eluting with 0-4% MeOH in DCM) to give8-[(1R,3R)-3-hydroxycyclohexyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(3A, 1.46 g, 50%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=8.57 (s, 1H), 7.53 (d, J=9.3 Hz, 1H), 6.58 (br d, J=9.3 Hz, 1H), 6.02(br s, 1H), 4.37 (t, J=2.6 Hz, 1H), 2.97 (br s, 1H), 2.66-2.61 (m, 3H),1.96-1.69 (m, 6H), 1.61 (br t, J=13.4 Hz, 2H). MS: 292 [M+H]⁺. Opticalrotation: [α]_(D) ²²+15.2 (c 1.8, MeOH).

Solid OXONE® (13.8 g, 22.4 mmol) was added in portions to a chilled (0°C.) solution of8-[(1R,3R)-3-hydroxycyclohexyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(3A, 2.18 g, 7.48 mmol) in THE (30 mL) and water (20 mL). The mixturewas stirred for 2 h, as it was allowed to gradually warm to ˜15° C. Thesolution was diluted with EtOAc (50 mL) and washed with water (50 mL).The organic layer was dried over sodium sulfate and concentrated to givean ˜3:1 mixture of sulfone8-[(1R,3R)-3-hydroxycyclohexyl]-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-oneand sulfoxide8-[(1R,3R)-3-hydroxycyclohexyl]-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one(3B, 1.80 g, 79%) as a light yellow solid. MS: 330 [M+Na]⁺ forsulfoxide; 346 [M+Na]⁺ for sulfone.

A solution of the sulfone/sulfoxide mixture prepared above (1.80 g, 5.6mmol), 4-amino-1-methanesulfonylpiperidine (CAS #402927-97-3, 2.08 g,11.7 mmol), and DIPEA (3.60 g, 34.9 mL) in DMSO (30 mL) was stirred in a60° C. oil bath for 2 h, then at room temperature overnight. The mixturewas partitioned between DCM (30 mL) and water (30 mL×2). The organiclayer was washed with sat. aq NaCl (30 mL), dried over sodium sulfate,and concentrated. The residue was purified by silica gel chromatography(eluting with 0-3% MeOH in DCM) to give8-[(1R,3R)-3-hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 3, 2.12 g, 90%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=8.38 (s, 1H), 7.41 (d, J=9.3 Hz, 1H), 6.32 (br d, J=8.3 Hz, 1H), 5.94(br d, J=9.0 Hz, 1H), 5.68 (br s, 1H), 4.34 (br s, 1H), 3.97 (br s, 1H),3.86-3.76 (m, 2H), 3.02-2.86 (m, 3H), 2.86-2.78 (m, 3H), 2.67 (br d,J=8.5 Hz, 1H), 2.21 (br d, J=11.5 Hz, 2H), 1.87-1.52 (m, 8H). MS: 444[M+Na]⁺. Optical rotation: [α]_(D) ²²+7.9 (c 0.11, CHCl₃). Chiralpurity: 99% ee. Chiral SFC/MS analysis was performed on a LuxCellulose-2 4.6×150 mm, 3 μm column heated to 40° C. and eluted with amobile phase of CO₂ and 40% EtOH (0.05% DEA) flowing at 2.5 mL/min. Theproduct peak had a retention time of 5.69 min.

Example 4:4-({6-(2-hydroxyethyl)-8-[(1R,2S)-2-methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-methylpiperidine-1-sulfonamide

A solution of LHMDS (1.0 M in THF, 3.58 mL, 3.58 mmol) was addeddropwise to a chilled (−78° C.) solution of ethyl γ-hydroxybutyrate (237mg, 1.79 mmol) in anhydrous THE (3 mL). The reaction was stirred for 20min, then a solution of4-{[(1R,2S)-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 6, 150 mg, 0.597 mmol) in THE (2 mL) was added dropwise.The mixture was gradually warmed to room temperature with stirring for18 h. The reaction was quenched with acetic acid (573 mg, 9.55 mmol) andpartitioned between water and EtOAc. The aqueous layer was furtherextracted with EtOAc (20 mL×3). The combined organic layers were washedwith sat. aq NaCl, dried over sodium sulfate, filtered, concentrated,and purified by silica gel chromatography (eluting with 0-2% MeOH inDCM) to give6-(2-hydroxyethyl)-8-[(1R,2S)-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(4A, 181 mg, 95%) as a yellow oil. MS: 320 [M+H]⁺.

Solid OXONE® (523 mg, 0.85 mmol) was added to a chilled (0° C.) solutionof6-(2-hydroxyethyl)-8-[(1R,2S)-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(4A, 181 mg, 0.567 mmol) in THE (6 mL) and water (3 mL). The resultingmixture was stirred at room temperature for 1 h. Water (10 mL) wasadded, and the mixture extracted with EtOAc (20 mL×3). The combinedorganics were washed with sat. aq NaCl, dried over sodium sulfate,filtered, and concentrated to a yellow solid (178.2 mg). LCMS showedthis to be a ˜4:3 mixture of sulfone and sulfoxide products. Thismixture was dissolved in DMSO (5 mL),4-amino-N-methylpiperidine-1-sulfonamide (Intermediate 9, 147 mg, 0.76mmol) and DIPEA (196 mg, 1.52 mmol) were added, and the resultingsolution stirred at 85° C. for 16 h. After cooling to rt, the mixturewas partitioned between water (15 mL) and EtOAc (20 mL×3). The combinedorganics were washed with sat. aq NaCl (20 mL×3), dried over sodiumsulfate, filtered, concentrated, and purified by silica gelchromatography (eluting with 0-3% MeOH in DCM). The material thusobtained (182 mg, 81% purity by LCMS) was further purified bypreparative HPLC [DuraShell 150×25 mm×5 μm column; water (0.05%NH₄OH)-ACN] to give4-({6-(2-hydroxyethyl)-8-[(1R,2S)-2-methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-methylpiperidine-1-sulfonamide(Example 4, 90 mg, 38%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃)δ=8.37 (s, 1H), 7.36 (s, 1H), 5.97 (q, J=8.9 Hz, 1H), 4.59-4.45 (m, 1H),4.08-3.93 (m, 1H), 3.83 (br s, 2H), 3.77-3.64 (m, 2H) 3.15-2.92 (m, 1H)2.80 (t, J=5.8 Hz, 2H), 2.74 (d, J=5.5 Hz, 3H), 2.72-2.60 (m, 1H),2.41-2.27 (m, 1H), 2.19-2.10 (m, 2H), 2.09-1.99 (m, 1H), 1.86 (d, J=11.8Hz, 1H), 1.73-1.47 (m, 3H), 0.75 (d, J=7.0 Hz, 3H). MS: 465 [M+H]⁺.Optical rotation: [α]_(D) ²²−10.3 (c 0.5 MeOH). Chiral purity: >99% ee.Chiral SFC/MS analysis was performed on a Chiracel OD-3 4.6×100 mm, 3 μmcolumn heated to 40° C. and eluted with a mobile phase of CO₂ and agradient of 5 to 40% EtOH (0.05% DEA) over 5.5 min, flowing at 2.8mL/min. Flow at 40% EtOH (0.05% DEA) was continued for 2.5 min to eluteany remaining counter ions. The product peak had a retention time of4.049 min.

Method B (Wittig Cyclization) Example 5:(+)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-oneExample 6:(−)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

To a cooled (−70° C.) solution of ethyl(diethoxyphosphoryl)(fluoro)acetate (407 μL, 2 mmol) in THE (15 mL)under a nitrogen atmosphere was added dropwise n-BuLi (1.6 M in hexanes,1.9 mL, 3 mmol), then the mixture was stirred at −70° C. for 40 min. Tothis solution was added a solution of(±)-4-{[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 1, 267 mg, 1 mmol) in THE (5 mL). The mixture was stirredand allowed to warm gradually to room temperature overnight. Thesolution was then cooled in an ice-water bath, EtOH (2 mL) was added,followed by sat. aq NaHCO₃ (10 mL) and EtOAc (80 mL). The layers wereseparated, the organic layer was dried over sodium sulfate, concentratedto dryness, and the residue purified by silica gel chromatography(eluting with 40% heptane/60% EtOAc) to give(±)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(5A, 218 mg, 71%). ¹H NMR (400 MHz, CDCl₃) δ=8.64 (s, 1H), 7.30 (d,J=7.5 Hz, 1H), 5.94 (t, J=8.4 Hz, 1H), 2.87-2.72 (m, 1H), 2.65 (s, 3H),2.36-2.25 (m, 1H), 2.18-2.07 (m, 2H), 2.02-1.92 (m, 1H), 1.91-1.83 (m,1H), 1.37 (td, J=6.9, 13.9 Hz, 1H), 1.17 (s, 3H). ¹⁹F NMR (377 MHz,CDCl₃) δ=−125.5 (s, 1F). MS: 310 [M+H]⁺.

To a solution of(±)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(5A, 374 mg, 1.2 mmol) in DCM (30 mL) was added mCPBA (70%, 313 mg, 1.27mmol) in one portion. The resulting mixture was stirred at roomtemperature for 30 min. The volatiles were removed under reducedpressure to give crude(±)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfinyl)-pyrido-[2,3-d]pyrimidin-7(8H)-one(5B), which was used immediately without further purification in thefollowing step. MS: 308 [M+H]⁺.

To the above crude(±)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one(5B, ˜1.2 mmol) was added DMSO (5 mL),4-amino-1-methanesulfonylpiperidine (CAS #402927-97-3, 237 mg, 1.33mmol), and DIPEA (0.42 mL, 2.42 mmol). The mixture was stirred at 60° C.(oil bath temperature) under nitrogen for 2 h. Acetic acid (69 μL) wasadded, and the entire reaction mixture was purified by chiralpreparative SFC on a Chiralpak AD-H 30 mm×250 mm column at 40° C. andeluted with a mobile phase of 42% MeOH w/0.05% diethylamine (v:v) in CO₂held at 100 bar, flowing at 90 mL/min, using UV detection at 340 nm.After lyophilization of the product fractions, Example 5 (peak 1, 178mg, 34%, >99% ee) and Example 6 (peak 2, 193 mg, 36%, ˜98% ee) wereobtained as off-white solids. The absolute stereochemistry of eachisomer was not determined, but optical rotation measurements wereobtained.

Example 5:(+)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one.¹H NMR (700 MHz, DMSO-d₆) δ=8.59 (br s, 1H), 7.85 (br s, 1H), 7.69 (d,J=7.0 Hz, 1H), 5.89 (br s, 1H), 4.41 (br s, 1H), 4.09-3.78 (m, 1H),3.68-3.44 (m, 2H), 3.01-2.69 (m, 6H), 2.17 (br s, 2H), 1.96 (br s, 2H),1.90-1.77 (m, 2H), 1.73-1.41 (m, 3H), 0.98 (br s, 3H). ¹⁹F NMR (377 MHz,DMSO-d₆) δ=−134.1 to −138.0 (m, 1F). MS 440 [M+H]⁺. Optical rotation:[α]_(D) ²²=+18.5 (c 0.1, CHCl₃). Chiral purity: >99% ee. Chiral SFC/MSanalysis was performed on a Chiralpak AD-3 4.6 mm×100 mm column at rt,eluted with a mobile phase of 70% CO_(2/30)% MeOH held at 120 bar andflowing at 4.0 mL/min. This peak had a retention time of 1.33 min.

Example 6:(−)-6-fluoro-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one.¹H NMR (700 MHz, DMSO-d6) δ=8.59 (br s, 1H), 7.84 (br s, 1H), 7.72-7.58(m, 1H), 5.89 (br s, 1H), 4.42 (br s, 1H), 4.06-3.84 (m, 1H), 3.63-3.48(m, 2H), 2.96-2.73 (m, 6H), 2.40-2.12 (m, 2H), 1.96 (brs, 2H), 1.87(brs, 2H), 1.73-1.41 (m, 3H), 0.97 (brs, 3H). ¹⁹F NMR (377 MHz, DMSO-d6)δ=−136.0 (d, J=144.2 Hz, 1F). MS: 440 [M+H]⁺. Optical rotation: [α]_(D)²²=−15.9 (c 0.2, CHCl₃). Chiral purity: ˜98% ee. Chiral SFC/MS analysiswas performed on a Chiralpak AD-3 4.6 mm×100 mm column at rt, elutedwith a mobile phase of 70% CO_(2/30)% MeOH held at 120 bar and flowingat 4.0 mL/min. This peak had a retention time of 2.47 min.

Method C (Heck Coupling/Cyclization) Example 7:(+)-6-(2,2-difluoroethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-oneExample 8:(−)-6-(2,2-difluoroethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid,3.76 g, 26.1 mmol) in DCM (100 mL) at 0° C. was added difluoroaceticanhydride (3.25 mL, 26 mmol) followed by triethylamine (9.09 mL, 65.2mmol). The cooling bath was removed and stirring continued at roomtemperature for 3 h. The reaction was poured into a separatory funnel,washed with 6N HCl and sat. aq. NaCl, dried over MgSO₄, and filtered.The filtrate was cooled to 0° C. and acidified with acetic acid (16.4mL, 287 mmol). To this mixture was then added sodium borohydride (2.17g, 57.4 mmol) in three portions over 0.5 h. The reaction was allowed tostand at 4° C. overnight, then quenched with sat. aq NaCl and stirredvigorously for 0.5 h. Additional water was added to dissolve solids, andthe layers were separated. The organic layer washed with sat. aq NaCland concentrated to give5-(2,2-difluoroethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7A, 2.78 g,51%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=6.50-6.17 (m,1H), 3.70 (t, J=6.2 Hz, 1H), 2.64 (ddt, J=5.1, 6.1, 15.6 Hz, 2H), 1.86(s, 3H), 1.81 (s, 3H).

A suspension of 5-(2,2-difluoroethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione(7A, 2.78 g, 12.51 mmol) in benzyl alcohol (10 mL, 97 mmol) was treatedwith N,N-dimethylmethyleneiminium iodide (Eschenmoser's salt, 5.86 g,31.7 mmol) and heated at 65° C. for 6 h. The mixture was poured intoMTBE and washed with water (2 x) and sat. aq NaCl. The organic layer wasconcentrated and purified by silica gel chromatography (eluting with0-20% EtOAc in heptane) to give benzyl4,4-difluoro-2-methylidenebutanoate (7B, 2.52 g, 89%) as a clear oil. ¹HNMR (400 MHz, CDCl₃) δ=7.40-7.35 (m, 5H), 6.44 (s, 1H), 5.84 (s, 1H),6.01 (tt, J=4.8, 56.9 Hz, 1H), 5.23 (s, 2H), 2.95-2.83 (m, 2H).

To a solution of 2,4-dichloro-5-bromo pyrimidine (0.735 g, 3.23 mmol) inACN (20 mL) was added (±)-(1R*,2R*)-2-amino-1-methylcyclopentanol(Intermediate 1b, 0.400 g, 3.47 mmol) and triethylamine (0.50 mL, 3.6mmol). The reaction was stirred at room temperature for 4 h, and thenconcentrated under vacuum. The resulting solid was purified by silicagel chromatography (eluting with 20-70% EtOAc in heptane) to give(±)-(1R*,2R*)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-1-methylcyclopentanol(7C, 0.774 g, 78%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=8.18 (s,1H), 5.48 (br s, 1H), 4.28 (s, 1H), 4.23 (ddd, J=5.7, 8.1, 10.1 Hz, 1H),2.36-2.26 (m, 1H), 2.05-1.98 (m, 1H), 1.93-1.69 (m, 3H), 1.63-1.52 (m,1H), 1.16 (s, 3H). MS: 306, 308 [M+H]⁺ (Br+Cl isotope splitting).

To a solution of(±)-(1R*,2R*)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-1-methylcyclopentanol(7C, 300 mg, 0.978 mmol) in DMSO (0.80 mL) was added4-amino-1-methanesulfonylpiperidine (CAS #402927-97-3, 250 mg, 1.40mmol) and DIPEA (0.20 mL, 1.15 mmol). The mixture was heated at 100° C.for 6 h and to 110° C. for 6 h more. The reaction was diluted with DCMand washed with water. The water layer was extracted with DCM, and thecombined organic layers were concentrated and purified by silica gelchromatography (eluting with 50-90% EtOAc in heptane) to give(±)-(1R*,2R*)-2-[(5-bromo-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)amino]-1-methylcyclopentanol(7D, 0.264 g, 60%) as a white solid. MS; 448, 450 [M+H]⁺ (Br isotopesplitting).

A solution of benzyl 4,4-difluoro-2-methylidenebutanoate (7B, 2.20 g,9.72 mmol),(±)-(1R*,2R*)-2-[(5-bromo-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)amino]-1-methylcyclopentanol(7D, 235 mg, 0.524 mmol), and triethylamine (0.290 mL, 2.10 mmol) in DMA(5.00 mL) was degassed by sparging with nitrogen for 15 min.Palladium(II) acetate (23.5 mg, 0.105 mmol) and tri(o-tolyl)phosphine(63.8 mg, 0.210 mmol) were added and the reaction heated at 100° C. for3 h. After cooling the solution to rt, MeOH (1.00 mL), DBU (1.0 mL, 6.4mmol), and sodium thiomethoxide (65 mg, 0.93 mmol) were added, and thereaction heated at 60° C. for 2 h. The resulting mixture wasconcentrated under vacuum and purified by silica gel chromatography(eluting with 0-10% MeOH in DCM). The resulting dark oil was furtherpurified by preparative SFC on a Nacalai Cosmosil 3-Hydroxyphenyl bondedcolumn (20×150 mm I.D., 5 μm particle size) at a flow rate of 60 mL/minand a gradient of 15-25% methanol in CO₂ at 3%/min, with pressure set at100 bar. The racemic mixture was separated by preparative SFC on aChiralpak AD-H column (250×21 mm I.D., 5 μm particle size) with 26%methanol in CO₂ at a of flow rate 60 mL/min and pressure set at 100 bar,affording Example 7 (peak 1, 18.54 mg, 7.2%, >99% ee) and Example 8(peak 2, 19.56 mg, 7.7%, >99% ee) as white powders. The absolutestereochemistry of each isomer was not determined, but optical rotationmeasurements were obtained.

Example 7:(+)-6-(2,2-difluoroethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one.¹H NMR (400 MHz, DMSO-d6, 80° C.) δ=8.58 (s, 1H), 7.70 (s, 1H), 7.48 (brs, 1H), 6.19 (td, J=5.1, 57.2 Hz, 1H), 5.89 (t, J=8.6 Hz, 1H), 4.04 (s,1H), 3.99 (br s, 1H), 3.68-3.55 (m, 2H), 3.10-2.99 (m, 2H), 2.87 (s,3H), 2.97-2.84 (m, 2H), 2.29-2.17 (m, 1H), 2.14-1.83 (m, 5H), 1.76-1.53(m, 3H), 1.00 (s, 3H). ¹⁹F NMR (377 MHz, DMSO-d6) δ=−114.9 to −114.2 (m,2F). MS; 486 [M+H]⁺. Optical rotation: [α]_(D) ²²+31.9° (c 0.1, MeOH).Chiral purity: >99% ee. Chiral SFC/MS analysis was performed on aChiralpak AD-3 (100×4.6 mm I.D., 3 μm) column eluted with 30% methanolin CO₂ and pressure set at 120 bar, flowing at 4 mL/min. This peak had aretention time of 0.91 min

Example 8:(−)-6-(2,2-difluoroethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one.¹H NMR (400 MHz, DMSO-d6, 80° C.) δ=8.58 (s, 1H), 7.70 (s, 1H), 7.47 (brs, 1H), 6.19 (td, J=4.8, 57.1 Hz, 1H), 5.89 (t, J=8.3 Hz, 1H), 4.04 (s,1H), 4.02-3.93 (m, 1H), 3.68-3.55 (m, 2H), 3.10-2.99 (m, 2H), 2.87 (s,3H), 2.98-2.81 (m, 2H), 2.29-2.17 (m, 1H), 2.14-1.82 (m, 5H), 1.76-1.50(m, 3H), 1.00 (s, 3H). ¹⁹F NMR (377 MHz, DMSO-d6) δ=−114.6 to −114.4 (m,2F). MS; 486 [M+H]⁺. Optical rotation: [α]_(D) ²²−19.3 (c 0.1, MeOH).Chiral purity: >99% ee. Chiral SFC/MS analysis was performed on aChiralpak AD-3 (100×4.6 mm I.D., 3 μm) column eluted with 30% methanolin CO₂ and pressure set at 120 bar, flowing at 4 mL/min. This peak had aretention time of 1.615 min.

Method D (Chlorination at C-6 after Cyclization)

Example 9:6-chloro-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)-piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

A solution of8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)-piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 2, 4.22 g, 10 mmol) and NCS (1.53 g, 11 mmol) in 2-MeTHF (100mL) was stirred in a 50° C. oil bath for 44 h. After cooling to roomtemperature, EtOH (1.75 mL, 30 mmol) was added and the mixture stirredat room temperature for 1 h. The solution was diluted with EtOAc (120mL) and washed with a mixture of water (15 mL) and sat. aq NaHCO₃ (15mL). The aqueous layer was further extracted with EtOAc (80 mL). Thecombined organic layers were washed with sat. aq NaCl (15 mL), driedover sodium sulfate, filtered, and concentrated to dryness. Ethanol (45mL) was added to the residue, and the resulting suspension stirred in a55° C. oil bath for 1 h, then allowed to gradually cool with stirring toroom temperature overnight. The resulting white solid was collected byfiltration, rinsed with EtOH (3 mL), and dried under vacuum (˜10 mmHg,50° C.) to give6-chloro-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 9, 3.86 g, 84%) as a white solid. ¹H NMR (400 MHz, DMSO-d6, 20°C.) δ=8.71-8.54 (m, 1H), 8.09 (s, 1H), 8.05-7.65 (m, 1H), 5.91 (t, J=8.2Hz, 1H), 4.46-4.28 (m, 1H), 4.03-3.81 (m, 1H), 3.65-3.48 (m, 2H),2.98-2.77 (m, 5H), 2.46-2.27 (m, 1H), 2.18 (d, J=10.3 Hz, 2H), 1.99-1.77(m, 4H), 1.75-1.37 (m, 3H), 0.96 (br s, 3H). ¹H NMR (400 MHz, DMSO-d6,80° C.) δ=8.60 (s, 1H), 8.02 (s, 1H), 7.61 (br s, 1H), 5.91 (dd, J=7.4,9.2 Hz, 1H), 4.09 (s, 1H), 4.04-3.94 (m, 1H), 3.70-3.49 (m, 2H),2.97-2.88 (m, 2H), 2.87 (s, 3H), 2.48-2.42 (m, 1H), 2.20 (dt, J=8.1,11.4 Hz, 1H), 2.09 (d, J=12.3 Hz, 1H), 2.05-1.96 (m, 2H), 1.96-1.84 (m,2H), 1.79-1.66 (m, 2H), 1.65-1.51 (m, 1H), 1.01 (s, 3H). MS: 456/458 (Clisotope pattern) [M+H]⁺. Optical rotation: [α]_(D) ²²−31.4 (c 0.4,MeOH). Chiral analysis: >99% ee. Chiral SFC/MS analysis was performed ona Phenomenex Lux Cellulose-1 4.6×100 mm 3p column at room temperatureand eluted with a mobile phase of 30% MeOH in CO₂ maintained at 120 baroutlet pressure, flowing at 4 mL/min. The product peak had a retentiontime of 1.52 min.

Method E (Di- and Tri-Fluoromethylation at C-6 after Cyclization)

Example 10:6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

A solution of zinc difluoromethanesulfinate (3.34 g, 11.4 mmol) and iron(II) chloride (377 mg, 1.90 mmol) in water (10 mL) was added portionwiseto a solution of8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 2, 1.60 g, 3.80 mmol) and TFA (0.290 mL, 3.80 mmol) in DMSO (60mL) at room temperature. The resulting mixture was treated with TBHP (70wt % solution in water, 0.400 mL, 342 mg, 3.80 mmol), causing a slightincrease in internal temperature to 32° C. Stirring was continued atroom temperature for 19 h, at which time LCMS showed ˜30% conversion. Asecond portion of TBHP solution (0.400 mL, 342 mg, 3.80 mmol was addedand stirring continued for 3 h. A third portion of TBHP solution (0.400mL, 342 mg, 3.80 mmol) was added and stirring continued at roomtemperature for 45 min, at which time LCMS showed ˜50% conversion. Morezinc difluoromethanesulfinate (1.1 g, 3.7 mmol) and TBHP solution (0.400mL, 342 mg, 3.80 mmol) were added, and the mixture stirred at roomtemperature for 20 h. At this time, LCMS showed ˜90% conversion. Thereaction solution was poured into a mixture of 10% aq sodium EDTA/ice,and extracted with EtOAc (50 mL). The aqueous layer was saturated withNaCl, and extracted further with EtOAc (50 mL×3). The combined organicswere washed with dilute aq sodium EDTA (50 mL) and sat. aq NaCl (50 mL).The deep blue organic layer was treated with activated charcoal andsodium sulfate, filtered, and evaporated to dryness. The residue (1.49 gfoam) was purified by preparative SFC (Diol/Monol column with MeOH/CO₂)to give6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methyl-sulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 10, 568 mg, 32%) as a white solid. ¹H NMR (400 MHz, DMSO-d6)δ=8.72 (s, 1H), 8.03 (s, 1H), 7.76 (br s, 1H), 7.00-6.50 (m, 1H), 5.87(t, J=8.3 Hz, 1H), 4.08 (s, 1H), 4.06-3.89 (m, 1H), 3.62 (t, J=11.7 Hz,2H), 2.98-2.89 (m, 2H), 2.87 (s, 3H), 2.57-2.51 (m, 1H), 2.27-2.14 (m,1H), 2.10 (d, J=9.4 Hz, 1H), 2.04-1.93 (m, 2H), 1.93-1.80 (m, 2H),1.76-1.69 (m, 2H), 1.69-1.55 (m, 1H), 1.03 (s, 3H). ¹⁹F NMR (377 MHz,DMSO-d6) δ=−125.7 to −113.3 (m, 2F). ¹³C NMR (101 MHz, DMSO-d6) Shift159.5, 159.2, 154.9, 133.4, 110.3, 102.6, 102.0, 78.9, 61.5, 45.8, 43.0,42.8, 40.2, 32.9, 28.5, 25.1, 22.2, 21.8. MS: 472 [M+H]⁺. Opticalrotation: [α]_(D) ²²−35.8 (c 0.7, MeOH); [α]_(D) ²²−25.3 (c 0.6, CHCl₃).Chiral SFC analysis: >99% ee. Retention time 2.78 min on Phenomenex LuxCellulose-1 4.6×100 mm 3p column (ambient temp); mobile phase: 15% MeOHin CO₂, 120 bar, 4 mL/min.

Example 133:(−)-6-(difluoromethyl)-8-[(1R*,3R*)-3-hydroxycyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-oneExample 134:(+)-6-(difluoromethyl)-8-[(1R*,3R*)-3-hydroxycyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

In a flow reactor set up according to the scheme provided in FIG. 5. thefollowing solutions were prepared and passed through the correspondingmixing valves at 1 mL/min: tert-butyl hydroperoxide (TBHP, 0.632 g, 4.91mmol, 0.675 mL) in 29 mL of DMSO; sodium difluoromethanesulfinate (882mg, 6.39 mmol) and iron sulfate (11.2 mg, 0.0737 mmol) in 3 ml ofwater+27 mL of DMSO; and(±)-8-[3-hydroxycyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(synthesized from Intermediate 8 by the method of Example 1, 500 mg,1.23 mmol) in 30 mL of DMSO.

The DMSO solution containing the product mixture was collected in asingle bottle. After the substrate solution was consumed, the productmixture was poured over a solution of ethylenediaminetetraacetic acid(1.080 g, 3.68 mmol) and sodium bicarbonate (2.4 g, 28.57 mmol) in 150mL of water and ice, and the resulting solution extracted with ethylacetate (3×100 mL). The organics were combined, washed with brine (3×100mL), dried over sodium sulfate and evaporated. The crude concentrate wasloaded into a silica column and eluted with ethyl acetate/heptane 0-80%.The fractions containing the product were combined and evaporated togive a yellow solid. The enantiomers were resolved by SFC using aChiralPak AD-H 21×250 mm column at 40° C. eluted with 20% IPA in CO₂ andheld at 120 bar at a flow of 85 mL/min.

Example 133:(−)-6-(difluoromethyl)-8-[(1R*,3R*)-3-hydroxycyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(82 mg, 15%) white solid. ¹H NMR (400 MHz, DMSO-d6) δ=8.76 (d, J=18.8Hz, 1H), 8.06 (s, 1H), 8.21-7.98 (m, 1H), 6.87 (t, J=55.5 Hz, 1H),6.23-6.02 (m, 1H), 4.64-4.50 (m, 1H), 4.43 (br. s., 1H), 4.12-3.83 (m,1H), 3.65-3.52 (m, J=6.6 Hz, 2H), 2.94-2.81 (m, 5H), 2.42-2.10 (m, 2H),2.09-1.87 (m, 3H), 1.75-1.52 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆)δ=−120.0 to −115.8 (m, 2F). MS: 485 [M+H]⁺, Optical rotation [α]_(D)²²−15.6 (c 0.1, MeOH); >99% ee. Retention time 1.828 min in a ChiralPakAD-3 4.6×100 mm 3p column, mobile phase 20% IPA; 120 bar at 4 mL/min.

Example 134:(+)-6-(difluoromethyl)-8-[(1R*,3R*)-3-hydroxycyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(76 mg, 14%) white solid. ¹H NMR (400 MHz, DMSO-d6) δ=8.76 (d, J=18.7Hz, 1H), 8.06 (s, 1H), 8.22-7.97 (m, 1H), 6.87 (t, J=55.3 Hz, 1H),6.21-6.01 (m, 1H), 4.64-4.51 (m, 1H), 4.43 (br. s., 1H), 4.13-3.83 (m,1H), 3.63-3.52 (m, J=5.9 Hz, 2H), 2.92-2.81 (m, 5H), 2.41-2.13 (m, 2H),2.11-1.89 (m, 3H), 1.75-1.53 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d6)δ=−121.8 to −115.6 (m, 2F). MS: 485 [M+H]⁺, Optical rotation [α]_(D)²²+14.8 (c 0.1, MeOH); >99% ee. Retention time 3.08 min in a ChiralPakAD-3 4.6×100 mm 3p column, mobile phase 20% IPA; 120 bar at 4 mL/min

Method F (Post-Cyclization Amidation and Dehydration to Nitrile) Example135:(8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetonitrile

Diethyl succinate (6.61 g, 37.9 mmol) was added dropwise to a cooled(−70° C.) solution of LiHMDS (1.0 M in THF, 75.8 mL, 75.8 mmol) in THE(100 mL). After stirring for 10 minutes, a solution of4-(cyclopentylamino)-2-(methylsulfanyl)pyrimidine-5-carbaldehyde[VanderWel, et al. J. Med. Chem. 2005, 48, 2371] (6.00 g, 25.3 mmol) inTHE (40 mL) was added and the mixture stirred at −70° C. for 30 minutes.The solution was allowed to warm to room temperature and stirredovernight. The mixture was partitioned between water (100 mL) and EtOAc(200 mL), and the aqueous layer further extracted with EtOAc (2×50 mL).No product was observed in the combined organic layers by TLC. Theaqueous layer was acidified to pH 2 with conc. HCl. The resultingprecipitate was collected by suction filtration, washed with water andpetroleum ether, dried under vacuum, and then purified by silica gelchromatography (eluting with 2-5% MeOH in DCM) to give2-(8-cyclopentyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)aceticacid (135A, 5.00 g, 62%) as a yellow solid.

A suspension of2-(8-cyclopentyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)aceticacid (135A, 5.00 g, 15.7 mmol) in EtOH (80 mL) was treated with conc.sulfuric acid (5 mL) and heated to 80° C. for 18 h, affording a clearyellow solution. After cooling to room temperature, the solution wasconcentrated to dryness, the residue dissolved in DCM (100 mL), andbasified to pH ˜8 with sat. aq. Na₂CO₃. The layers were separated andthe aqueous layer further extracted with DCM (2×50 mL). The combinedorganics were dried over sodium sulfate, filtered, concentrated, andpurified by silica gel chromatography (eluting with 0-20% EtOAc in DCM)to give ethyl2-(8-cyclopentyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetate(135B, 4.90 g, 90%) as a yellow solid.

By the method of Example 1, 135B was used to produce ethyl2-(8-cyclopentyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetate(135C, ˜87% purity) as a crude yellow gum. A sample of this crude gum(150 mg, 0.31 mmol) was dissolved in methanol (6 mL), and anhydrousgaseous ammonia bubbled in for 10 minutes. The mixture was stirred at80° C. overnight. After cooling to room temperature, the solvent wasevaporated, and the residue purified by preparative HPLC [column:DuraShell 150*25 mm*5 um; mobile phase: from 25% ACN in water (0.05%ammonium hydroxide v/v) to 45% ACN in H₂O (0.05% ammonium hydroxidev/v)] to give2-(8-cyclopentyl-2-((1-(methylsulfonyl)-piperidin-4-yl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetamide(135D, 40 mg, 28%) as white solid. ¹H NMR (400 MHz, DMSO-d6) δ=8.59 (s,1H), 7.85-7.49 (m, 2H), 7.35 (s, 1H), 6.86 (s, 1H), 5.93-5.75 (m, 1H),4.07-3.80 (m, 1H), 3.57 (d, J=11.0 Hz, 2H), 3.25 (s, 2H), 2.93-2.82 (m,5H), 2.17 (m, 2H), 1.98 (m, 4H), 1.79-1.55 (m, 6H). MS: 448.9 [M+H]⁺.

A second run (135C, 260 mg, 0.54 mmol), in ethanol (120° C. for 12 h)yielded crude 135D (200 mg of ˜60% purity) as a brown solid, which wasused without purification in the subsequent dehydration reaction.

A cooled (0° C.) solution of crude2-(8-cyclopentyl-2-((1-(methylsulfonyl)-piperidin-4-yl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetamide(135D, 100 mg, 0.13 mmol) and triethylamine (67.7 mg, 0.67 mmol) in DCM(5 mL) was treated with trifluoroacetic acid anhydride (56.2 mg, 0.27mmol). The cooling bath was removed and the mixture stirred at roomtemperature for 2 h. The resulting yellow suspension was washed withdeionized water (20 mL), then with sat. aq. NaCl. The organic layer wasdried over magnesium sulfate, filtered, and concentrated. This crudeproduct was combined with that from another run (starting with 80 mg,0.11 mmol, of 135D) for purification by preparative HPLC [column:DuraShell 150*25 mm*5 um; mobile phase: from 36% ACN in water (0.05%ammonium hydroxide v/v) to 56% ACN in H₂O (0.05% ammonium hydroxidev/v)] to give(8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetonitrile(Example 135, 27.1 mg, 26% yield for the combined batches) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ=8.49 (s, 1H), 7.70 (s, 1H), 5.87 (quin,J=8.9 Hz, 1H), 5.42 (br s, 1H), 4.05 (br s, 1H), 3.92-3.73 (m, 2H), 3.66(d, J=1.0 Hz, 2H), 2.95 (br s, 2H), 2.85 (s, 3H), 2.32 (br s, 2H), 2.21(br d, J=9.8 Hz, 2H), 2.04 (br s, 2H), 1.86 (br d, J=9.5 Hz, 2H), 1.70(br s, 4H). MS: 431 [M+H]⁺.

Method G (Post-Cyclization Functionalization of Piperidine) Example 136:8-cyclopentyl-6-(2-hydroxyethyl)-2-{[1-(propan-2-ylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

8-Cyclopentyl-6-(2-hydroxyethyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(136A), was synthesized from4-(cyclopentylamino)-2-(methylsulfanyl)pyrimidine-5-carbaldehyde[VanderWel, et al. J. Med. Chem. 2005, 48, 2371] andethyl-γ-hydroxybutyrate by the method of Example 4. A solution of 136A(95 mg, 0.284 mmol), tert-butyl 4-aminopiperidine-1-carboxylate [CAS#87120-72-7] (78.9 mg, 0.394), and DIPEA (0.187 mL, 1.13 mmol) in DMSO(2.5 mL) was heated at 65° C. for 15 h. The mixture was cooled to roomtemperature and diluted with water (8 mL), EtOAc (5 mL) and 4 M NaOH (1mL) and separated. The organic layer was concentrated to give crudetert-butyl4-((8-cyclopentyl-6-(2-hydroxyethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate(136B, 130 mg, 100%) which was used without further purification. MS:458 [M+H]⁺.

Trifluoroacetic acid (2.0 mL, 26 mmol) was added to a solution of crudetert-butyl4-((8-cyclopentyl-6-(2-hydroxyethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)-amino)piperidine-1-carboxylate(136B, 130 mg, 0.284 mmol) in dichloromethane (6 mL). The mixture wasstirred at room temperature for 30 minutes, then concentrated todryness. The residue was dissolved in dichloromethane (6 mL).Triethylamine (0.238 mL, 1.70 mmol) and isopropylsulfonyl chloride(0.035 mL, 0.313 mmol) were added, and the mixture stirred at roomtemperature. After 20 minutes, more isopropylsulfonyl chloride (0.015mL, 0.134 mmol) was added, and after another 20 min an additional amountof isopropylsulfonyl chloride (0.030 mL, 0.269 mmol) was added. Themixture was stirred for 15 more minutes, then was quenched with 4 N NaOH(0.6 mL) and stirred vigorously. Extraction with dichloromethane andpurification by preparative SFC afforded8-cyclopentyl-6-(2-hydroxyethyl)-2-{[1-(propan-2-ylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 136, 28.3 mg, 22%) as a solid. ¹H NMR (400 MHz, DMSO-d6, 80°C.) δ=8.51 (s, 1H), 7.51 (s, 1H), 7.30 (d, J=4.4 Hz, 1H), 5.85 (quin,J=8.9 Hz, 1H), 3.99 (br s, 1H), 3.70 (d, J=13.0 Hz, 2H), 3.63 (t, J=6.5Hz, 2H), 3.31 (td, J=6.8, 13.6 Hz, 1H), 2.62 (t, J=6.5 Hz, 2H), 2.32 (brs, 2H), 2.06-1.91 (m, 4H), 1.83-1.71 (m, 2H), 1.70-1.56 (m, 4H), 1.27(d, J=6.7 Hz, 6H). 1H obscured by H₂O. MS: 464 [M+H]⁺.

Method H (Curtius Rearrangement at C-6) Example 137:6-amino-2-{[1-(but-3-yn-1-ylsulfonyl)piperidin-4-yl]amino}-8-cyclopentylpyrido[2,3-d]pyrimidin-7(8H)-one

Diphenyl phosphoryl azide (5.41 g, 19.6 mmol) was added to a roomtemperature solution of8-cyclopentyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylicacid [Toogood, et al. J. Med. Chem., 2005, 48, 2388-2406] (5.0 g, 16.37mmol) and triethylamine (1.99 g, 19.6 mmol) in tert-butanol (60 mL). Theresulting suspension was stirred at 79° C. for 18 h. The solids wereremoved by filtration. The filter cake was rinsed with ethyl acetate (50mL) and the combined filtrates concentrated and purified by silica gelchromatography (eluting with pet. ether/ethyl acetate) to givetert-butyl(8-cyclopentyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-carbamate(137A, 4.1 g, 67%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃):δ=8.60 (s, 1H), 8.15 (s, 1H), 7.80 (s, 1H), 6.04-6.00 (m, 1H), 2.59 (s,3H), 2.30-2.27 (m, 2H), 2.07-2.05 (m, 2H), 1.91-1.89 (m, 2H), 1.71-1.69(m, 2H), 1.50 (s, 9H). MS: 377 [M+H]⁺.

To a solution of tert-butyl(8-cyclopentyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)carbamate(137A, 495 mg, 1.3 mmol) in DCM (13 mL) was added mCPBA (˜70%, 389 mg,1.58 mmol). The mixture was stirred at room temperature for 1 hour. Thereaction was diluted with DCM (30 mL), and washed with saturated Na₂SO₃(10 mL) and then with saturated aqueous NaHCO₃ (10 mL). The organiclayer was dried over sodium sulfate and evaporated to give a white solidwhich was a 9:1 mixture of sulfoxide and sulfone intermediates. MS: 393([M+H]⁺ sulfoxide) and 409 ([M+H]⁺ sulfone). A portion of this mixture(235 mg, 0.6 mmol) was dissolved in DMSO (3 mL). Diisopropylethyl amine(0.52 mL, 3 mmol) and 1-(but-3-yn-1-ylsulfonyl)piperidin-4-aminemethanesulfonate (Intermediate 13, 225 mg, 0.72 mmol) were added. Themixture was heated at 55° C. for 16 h, then at 65° C. for 3 h. Aftercooling to room temperature, the reaction mixture was partitionedbetween saturated aqueous NaHCO₃ (10 mL) and DCM (30 mL). The organiclayer was dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (eluting with ethyl acetate/heptane) to givetert-butyl(2-((1-(but-3-yn-1-ylsulfonyl)piperidin-4-yl)amino)-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)carbamate(137B, 166 mg, 51%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ=8.65(br s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.75-7.36 (m, 1H), 5.92 (br s,1H), 4.02-3.80 (m, 1H), 3.62 (d, J=12.5 Hz, 2H), 3.28-3.23 (m, 2H),3.08-2.92 (m, 3H), 2.59 (dt, J=2.7, 7.5 Hz, 2H), 2.37-2.09 (m, 2H),2.02-1.91 (m, 4H), 1.79 (d, J=4.6 Hz, 2H), 1.71-1.53 (m, 4H), 1.47 (s,9H). MS: 545 [M+H]⁺.

A solution of tert-butyl(2-((1-(but-3-yn-1-ylsulfonyl)piperidin-4-yl)amino)-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)carbamate(137B, 166 mg, 0.29 mmol) and methanesulfonic acid (195 μL, 2.9 mmol) inDCM (10 mL) was stirred at room temperature for 1 hour. The solution wasconcentrated to dryness, and the residue treated with ice (10 g) andsaturated aqueous NaHCO₃ (10 mL), causing some gas evolution. Theresulting suspension was stirred at room temperature for 1 hour, thenthe solids collected by filtration. The precipitate was washed withwater and dried in a vacuum oven (45° C., 10 mmHg) to give6-amino-2-{[1-(but-3-yn-1-ylsulfonyl)piperidin-4-yl]amino}-8-cyclopentylpyrido[2,3-d]pyrimidin-7(8H)-one(Example 137, 119 mg, 91%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ=8.41 (s, 1H), 7.16 (br s, 1H), 6.62 (s, 1H), 5.93 (t, J=8.7Hz, 1H), 5.70-4.31 (m, 2H), 3.89 (br s, 1H), 3.61 (d, J=12.5 Hz, 2H),3.28-3.24 (m, 2H), 3.07-2.94 (m, 3H), 2.59 (dt, J=2.4, 7.4 Hz, 2H),2.30-2.21 (m, 2H), 2.08-1.89 (m, 4H), 1.85-1.70 (m, 2H), 1.68-1.44 (m,4H). MS: 445 [M+H]⁺.

Method I (Pd-Catalyzed Cross-Coupling at C-6) Example 138:8-cyclopentyl-6-ethenyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

6-Bromo-8-cyclopentyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one(138A) was synthesized from6-bromo-8-cyclopentyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one[Toogood, et al. J. Med. Chem., 2005, 48, 2388-2406] by the method ofExample 1. ¹H NMR (400 MHz, DMSO-d6) δ=8.55-8.68 (m, 1H), 8.25 (s, 1H),7.79-8.09 (m, 1H), 5.74-6.10 (m, 1H), 3.80-4.16 (m, 1H), 3.57 (d, J=11.2Hz, 2H), 2.76-3.00 (m, 5H), 2.20-2.35 (m, 1H), 2.15 (br s, 1H), 1.97 (brs, 4H), 1.77 (br s, 2H), 1.61 (d, J=11.4 Hz, 4H). MS: 470/472 (Brisotope splitting, [M+H]⁺.

A solution of6-Bromo-8-cyclopentyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one(138A, 5.00 g, 12.0 mmol) and tri-n-butyl(ethenyl)stannane (3.80 g, 12.0mmol) in THE (100 mL, 0.1 M) was degassed with nitrogen, then palladiumtetrakis(triphenylphospine) (692 mg, 0.599 mmol) was added. The mixturewas heated at 65° C. for 48 h. The volatiles were removed under reducedpressure and the residue purified on silica (eluting 0-20% ethylacetate/dichloromethane). The product was then recrystallized fromDCM/diethyl ether ( 1/10, 50 mL) to give8-cyclopentyl-6-ethenyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 138, 2.5 g, 50%), still containing 10% triphenylphosphineoxide.

For biological testing, a sample of this batch (102 mg, 0.244 mmol) wasfurther purified by preparative SFC to give analytically pure8-cyclopentyl-6-ethenyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 138, 76.48 mg, 75% recovery) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ=8.44 (s, 1H), 7.55 (s, 1H), 6.89 (dd, J=11.25, 17.73 Hz, 1H),5.79-5.99 (m, 2H), 5.12-5.44 (m, 2H), 3.95-4.17 (m, 1H), 3.81 (d, J=12.2Hz, 2H), 2.90-3.06 (m, 2H), 2.84 (s, 3H), 2.27-2.47 (m, 2H), 2.21 (dd,J=3.06, 13.08 Hz, 2H), 2.00-2.13 (m, 2H), 1.80-1.91 (m, 2H), 1.64-1.79(m, 4H). MS: 418 [M+H]⁺.

Example 139:8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-6-(prop-2-en-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a vial with a stir bar was added6-Bromo-8-cyclopentyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one(138A, 470 mg, 1 mmol), DME (10 mL, 0.1 M),4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane (281 μL, 1.5mmol), CsF (304 mg, 2 mmol), and PdCl₂(dppf) (37 mg, 0.05 mmol). Themixture was degassed with nitrogen for 1 minute, then the vial wascapped and placed in an 80° C. heating block for 16 h. The reaction wasdiluted with ethyl acetate (100 mL) and saturated aqueous NaHCO₃ (20mL). The organic layer was separated and the product was extracted withethyl acetate (20 mL). The combined organic layers were dried oversodium sulfate, concentrated, and purified on silica (eluted withheptane/ethyl acetate) to give8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-6-(prop-2-en-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(Example 139, 154 mg, 40%) as a light-colored solid. ¹H NMR (400 MHz,DMSO-d6) δ=8.58 (br s, 1H), 7.48 (s, 1H), 5.95 (tdd, J=6.69, 10.16,17.04 Hz, 1H), 5.05-5.19 (m, 2H), 3.57 (d, J=12.2 Hz, 3H), 3.18 (d,J=6.6 Hz, 2H), 2.79-2.96 (m, 7H), 1.99 (s, 6H), 1.53-1.69 (m, 4H). MS:432 [M+H]⁺.

Method J (Radical Addition at C-6) Example 140:6-(2,2-difluoroethyl)-8-[(1R,3R)-3-hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution8-[(1R,3R)-3-hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 3, 0.161 g, 0.382 mmol) in DMSO (1.5 mL) was added(4,4′-di-t-butyl-2,2′-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(II)hexafluorophosphate (0.012 g, 0.0107 mmol), 1,1-difluoro-2-iodoethane(0.27 mL, 3.1 mmol), potassium carbonate (0.150 g, 0.960 mmol) andtriethylamine (30 μL, 0.22 mmol). Nitrogen was bubbled through themixture for ten minutes, and then the vial was sealed. The reaction wasirradiated with blue light (Kessil, H150-Blue, 34W) for 16 h. Thereaction was filtered and concentrated, and the residue purified bypreparative HPLC (Waters SFC 200 Glacier/2-Cosmosil 3HOP 150×21.1 mmI.D., 5 um columns. co-solvent methanol. 14% B for 2.5 min, to 22% in7.5 min, to 50% in 1 min, hold 1 min @ 100 bar, 35 C, 80 g/min.) to give6-(2,2-difluoroethyl)-8-[(1R,3R)-3-hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 140, 29.35 mg, 16% yield). ¹H NMR (400 MHz, DMSO-d6) δ=8.58 (s,1H), 7.85 (d, J=7.0 Hz, 1H), 7.70 (s, 1H), 6.22 (tt, J=4.8, 57.2 Hz,1H), 4.46 (br s, 1H), 4.12 (br s, 1H), 3.99 (br s, 1H), 3.66-3.55 (m,2H), 3.02 (dt, J=4.0, 17.1 Hz, 2H), 2.89 (s, 3H), 2.87-2.77 (m, 2H),2.18-1.38 (m, 11H). MS: 486 [M+H]⁺. [α]_(D) ²²+18.0 (c 0.1, MeOH).

Additional compounds of the invention were prepared by modifications ofthe methods exemplified herein. Except where otherwise indicated, allcompounds having chiral centers were prepared and/or isolated as asingle enantiomer having a known relative configuration. Compoundsmarked “absolute stereochemistry unknown” were typically prepared fromracemic intermediates and resolved into single enantiomers by anappropriate chiral preparative SFC method before characterization andtesting. Where the absolute stereochemistry is unknown for a pair ofenantiomers, the stereochemistry represented in Table 1 is assignedbased on the sign of the optical rotation ([α]_(D) ²⁰) and the relativebiological activity, by analogy to compounds having known absoluteconfigurations. Compounds marked “absolute stereochemistry known” weretypically prepared from chiral intermediates having knownstereochemistry.

Selected compounds and their corresponding characterization data arepresented in Table 1 below.

TABLE 1 Ex. No. LCMS ¹H NMR (ppm); ¹⁹F NMR (ppm); optical (Method)Structure/IUPAC name [M + H]⁺ rotation; stereochem. notes 1-10 inmethods text 11 (A)

407 ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H),6.36 (d, J = 9.3 Hz, 1H), 5.84 (quin, J = 9.0 Hz, 1H), 5.53-5.12 (m,1H), 4.23-4.15 (m, 1H), 4.04 (br s, 1H), 3.74 (d, J = 12.8 Hz, 2H),3.09-2.97 (m, 2H), 2.76 (d, J = 5.3 Hz, 3H), 2.37 (br s, 2H), 2.16 (dd,J = 3.5, 13.1 Hz, 2H), 2.07-1.97 (m, 2H), 1.91- 1.80 (m, 2H), 1.75-1.63(m, 4H) 4-[(8-cyclopentyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino]-N-methylpiperidine-1- sulfonamide 12 (A)

421 ¹H NMR (400 MHz, CDCl₃) δ = 8.40 (s, 1H), 7.42 (d, J = 9.3 Hz, 1H),6.37 (d, J = 9.3 Hz, 1H), 5.84 (quin, J = 8.9 Hz, 1H), 5.31 (br s, 1H),4.04 (br s, 1H), 3.72 (d, J = 13.1 Hz, 2H), 3.11-2.98 (m, 2H), 2.85 (s,6H), 2.37 (br s, 2H), 2.14 (dd, J = 3.5, 13.1 Hz, 2H), 2.03 (d, J = 7.0Hz, 2H), 1.91-1.79 (m, 2H), 1.75-1.62 (m, 4H)4-[(8-cyclopentyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino]-N,N-dimethylpiperidine-1- sulfonamide 13 (A)

393 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.61- 8.58 (m, 1H), 7.87-7.66 (m, 2H),6.78 (s, 2H), 6.24-6.21 (m, 1H), 5.87-5.73 (m, 1H), 3.89-3.79 (m, 1H),3.48 (m, 2H), 2.65-2.60 (m, 2H), 2.36-2.18 (m, 2H), 1.97 (m, 4H),1.73-1.56 (m, 6H) 4-[(8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino]piperidine-1-sulfonamide 14(A)

428 ¹H NMR (400 MHz, CDCl₃) δ = 8.40 (s, 1H), 7.42 (d, J = 9.0 Hz, 1H),6.42-6.30 (m, 1H), 6.23 (s, 1H), 5.83 (quin, J = 8.9 Hz, 1H), 5.40 (brs, 1H), 4.11 (br s, 1H), 3.99 (d, J = 13.1 Hz, 2H), 3.29 (t, J = 11.5Hz, 2H), 2.35 (br s, 2H), 2.24-2.13 (m, 2H), 2.02 (d, J = 6.5 Hz, 2H),1.91-1.78 (m, 2H), 1.67 (br s, 4H) ¹⁹F NMR (377 MHz, DMSO-d₆) δ = −123.3(br s, 2F) 8-cyclopentyl-2-({1- [(difluoromethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 15 (A)

436 ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.41 (d, J = 9.5 Hz, 1H),6.36 (d, J = 9.3 Hz, 1H), 5.84 (quin, J = 8.9 Hz, 1H), 5.37 (br s, 1H),4.12-3.96 (m, 1H), 3.84-3.71 (m, 4H), 3.45-3.37 (m, 3H), 3.23 (t, J =5.8 Hz, 2H), 3.10-2.95 (m, 2H), 2.38 (br s, 2H), 2.15 (dd, J = 3.5, 13.1Hz, 2H), 2.02 (br s, 2H), 1.91-1.79 (m, 2H), 1.68 (d, J = 7.5 Hz, 4H)8-cyclopentyl-2-({1-[(2- methoxyethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 16 (A)

406 ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H),6.36 (d, J = 9.3 Hz, 1H), 5.84 (quin, J = 9.0 Hz, 1H), 5.33 (br s, 1H),4.04 (br s, 1H), 3.83 (d, J = 12.8 Hz, 2H), 3.09-2.92 (m, 4H), 2.45-2.24(m, 2H), 2.22-2.12 (m, 2H), 2.03 (br s, 2H), 1.91-1.79 (m, 2H),1.63-1.62 (m, 1H), 1.77-1.62 (m, 3H), 1.39 (t, J = 7.4 Hz, 3H)8-cyclopentyl-2-{[1- (ethylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 17 (A)

450 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.55 (s, 1H), 7.63 (d, J = 9.3Hz, 1H), 7.43 (d, J = 5.4 Hz, 1H), 6.20 (d, J = 9.3 Hz, 1H), 5.81 (quin,J = 8.9 Hz, 1H),4.45 (br s, 1H), 4.05-3.90 (m, 1H), 3.64 (td, J = 3.4,12.0 Hz, 2H), 3.14 (s, 2H), 3.01- 2.91 (m, 2H), 2.39-2.26 (m, 2H), 2.03-1.92 (m, 4H), 1.84-1.72 (m, 2H), 1.71- 1.58 (m, 4H), 1.34 (s, 6H)8-cyclopentyl-2-({1-[(2-hydroxy-2- methylpropyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 18 (A)

470 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.55 (s, 1H), 7.63 (d, J = 9.3Hz, 1H), 7.45 (d, J = 6.1 Hz, 1H), 6.20 (d, J = 9.3 Hz, 1H), 5.81 (quin,J = 8.9 Hz, 1H), 5.11 (s, 2H), 4.04-3.92 (m, 1H), 3.74 (td, J = 3.4,12.8 Hz, 2H), 3.18 (s, 3H), 3.15- 3.05 (m, 2H), 2.39-2.27 (m, 2H), 2.04-1.92 (m, 4H), 1.84-1.73 (m, 2H), 1.73- 1.59 (m, 4H) 8-cyclopentyl-2-[(1-{[(methylsulfonyl)methyl]sulfonyl}piperi-din-4-yl)amino]pyrido[2,3-d]pyrimidin- 7(8H)-one 19 (A)

420 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.56 (br s, 1H), 7.86 (br s, 1H), 7.66(d, J = 9.2 Hz, 1H), 6.35-6.12 (m, 1H), 5.68-5.21 (m, 1H), 4.03-3.75 (m,1H), 3.60 (br s, 2H), 2.92-2.80 (m, 5H), 2.59 (d, J = 9.9 Hz, 1H), 2.37(br s, 1H), 2.10-1.94 (m, 2H), 1.76 (br s, 2H), 1.70-1.54 (m, 8H), 1.49(br s, 2H) 8-cycloheptyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 20 (A)

435 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.42-7.39 (d, J = 9.2 Hz,1H), 6.39- 6.34 (m, 1H), 5.56-5.31 (m, 2H), 4.18- 4.17 (m, 1H), 4.07 (m,1H), 3.78-3.75 (m, 2H), 3.06-3.01 (t, J = 11.0 Hz, 2H), 2.77 (d, J = 5.6Hz, 3H), 2.59-2.56 (m, 2H), 2.20-2.18 (m, 2H), 1.77-1.64 (m, 10H),1.55-1.46 (m, 2H) 4-[(8-cycloheptyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino]-N-methylpiperidine-1-sulfonamide 21 (A)

421 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.56 (s, 1H), 7.86 (m, 1H), 7.65 (d, J= 8.8 Hz, 1H), 6.84-6.78 (m, 2H), 6.24-6.18 (m, 1H), 5.56-5.28 (m, 1H),3.86-3.72 (m, 1H), 3.51 (br s, 2H), 2.62-2.59 (m, 2H), 1.99 (m, 2H),1.75 (m, 2H), 1.62-1.49 (m, 12H) 4-[(8-cycloheptyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino]piperidine-1-sulfonamide 22(A)

406 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.52 (br s, 1H), 7.55 (br s, 2H),6.00-5.73 (m, 1H), 4.06-3.76 (m, 1H), 3.56 (br s, 2H), 2.96-2.80 (m,5H), 2.37-2.11 (m, 2H), 2.05-1.90(m, 7H), 1.74 (br s, 2H), 1.67- 1.47(m, 4H) 8-cyclopentyl-6-methyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 23 (A)

421 ¹H NMR (400 MHz, CDCl₃) δ = 8.35 (s, 1H), 7.30 (d, J = 1.3 Hz, 1H),5.89 (quin, J = 8.9 Hz, 1H), 5.28 (br s, 1H), 4.20 (q, J = 5.3 Hz, 1H),4.02 (br s, 1H), 3.73 (d, J = 12.5 Hz, 2H), 3.10-2.97 (m, 2H), 2.77 (d,J = 5.3 Hz, 3H), 2.35 (br s, 2H), 2.22- 2.12 (m, 5H), 2.04 (m, 2H),1.91-1.78 (m, 2H), 1.68 (m, 4H) 4-[(8-cyclopentyl-6-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino]-N-methylpiperidine-1-sulfonamide 24 (A)

435 ¹H NMR (400 MHz, CDCl₃) δ = 8.35 (s, 1H), 7.30 (d, J = 1.3 Hz, 1H),5.89 (quin, J = 8.9 Hz, 1H), 5.24 (br s, 1H), 4.03 (d, J = 5.8 Hz, 1H),3.72 (d, J = 13.3 Hz, 2H), 2.98-3.11 (m, 2H), 2.84 (s, 6H), 2.33 (d, J =12.0 Hz, 2H), 2.10-2.19 (m, 5H), 2.00-2.09 (m, 2H), 1.78-1.91 (m, 2H),1.68-1.76 (m, 2H), 1.56-1.65 ppm (m, 2H)4-[(8-cyclopentyl-6-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino]-N,N-dimethylpiperidine-1- sulfonamide 25 (A)

407 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.50 (s, 1H), 7.66-7.53 (m, 2H), 6.77(s, 2H), 5.87-5.78 (m, 1H), 3.84-3.77 (m, 1H), 3.60-3.52 (m, 2H),2.65-2.59 (m, 2H), 2.32-2.16 (m, 2H), 2.02-1.96 (m, 7H), 1.72-1.54 (m,6H) 4-[(8-cyclopentyl-6-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino]piperidine-1-sulfonamide 26(A)

442 ¹H NMR (400 MHz, CDCl₃) δ = 8.35 (s, 1H), 7.31 (s, 1H), 5.88 (quin,J = 8.9 Hz, 1H), 5.22 (br s, 1H), 4.11 (br s, 1H), 3.98 (d, J = 13.6 Hz,2H), 3.30 (t, J = 11.5 Hz, 2H), 2.33 (br s, 2H), 2.23-2.13 (m, 5H), 2.05(br s, 2H), 1.90-1.79 (m, 2H), 1.74-1.63 (m, 4H) ¹⁹F NMR (377 MHz,DMSO-d₆) δ = −123.2 (s, 2F) 8-cyclopentyl-2-({1-[(difluoromethyl)sulfonyl]piperidin-4- yl}amino)-6-methylpyrido[2,3-d]pyrimidin-7(8H)-one 27 (A)

488 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.37 (s, 1H),5.88 (quin, J = 8.9 Hz, 1H), 5.58-5.06 (m, 1H), 4.12-3.95 (m, 1H), 3.86(d, J = 4.8 Hz, 2H), 3.76-3.60 (m, 2H), 3.10-2.97 (m, 3H), 2.86-2.79 (m,8H), 2.34 (br s, 2H), 2.14 (dd, J = 3.3, 13.1 Hz, 2H), 2.09-1.95 (m,2H), 1.92- 1.77 (m, 2H), 1.71-1.54 (m, 4H)4-{[8-cyclopentyl-6-(2-hydroxyethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-N,N-dimethylpiperidine-1- sulfonamide 28

407 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.40 (s, 1H), 7.13 (d, J = 4.6 Hz,1H), 6.60 (s, 1H), 6.02-5.85 (m, 1H), 5.15 (s, 2H), 3.86 (br s, 1H),3.55 (d, J = 12.1 Hz, 2H), 2.93-2.80 (m, 2H), 2.88 (s, 3H), 2.28 (d, J =10.4 Hz, 2H), 1.97 (d, J = 11.0 Hz, 4H), 1.83-1.71 (m, 2H), 1.69-1.51(m, 4H) 6-amino-8-cyclopentyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 29 (D)

426 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.68- 8.51 (m, 1H), 8.04 (br s, 1H),8.01-7.58 (m, 1H), 6.09-5.70 (m, 1H), 4.12-3.76 (m, 1H), 3.63-3.56 (m,2H), 2.87 (d, J = 11.3 Hz, 5H), 2.25 (br s, 1H), 2.12 (br s, 1H), 1.95(br s, 4H), 1.77 (br s, 2H), 1.68-1.51 (m, 4H)6-chloro-8-cyclopentyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 30 (E)

442 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.72 (s, 1H), 8.02 (s, 1H),7.77 (br s, 1H), 6.84 (t, J = 55.0 Hz, 1H), 5.83 (quin, J = 8.7 Hz, 1H),4.01 (br s, 1H), 3.63 (d, J = 12.3 Hz, 2H), 2.97-2.90 (m, 2H), 2.88 (s,3H), 2.32 (br s, 2H), 2.08-1.92 (m, 4H), 1.87-1.74 (m, 2H), 1.74-1.58(m, 4H) ¹⁹F NMR (377 MHz, DMSO-d₆, 80° C.) δ = −116.8 (br s, 2F)8-cyclopentyl-6-(difluoromethyl)-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 31 (A)

486 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.65 (s, 1H), 7.85 (s, 1H),7.56 (br s, 1H), 5.72-5.87 (m, 1H), 3.90-4.10 (m, 1H), 3.56-3.68 (m,2H), 2.89-2.96 (m, 2H), 2.88 (s, 3H), 2.22-2.36 (m, 2H), 1.94-2.07 (m,4H), 1.56-1.84 (m, 6H) ¹⁹F NMR (377 MHz, DMSO-d₆) δ = −100.9 (br s, 2F)(8-cyclopentyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)(difluoro)acetic acid 32 (A)

436 ¹H NMR (400 MHz, CDCl₃) δ = 8.34 (s, 1H), 7.30 (s, 1H), 5.97 (br s,1H), 5.38 (br s, 1H), 4.35 (br s, 1H), 3.97 (br s, 1H), 3.81 (dd, J =5.3, 10.3 Hz, 2H), 3.01-2.88 (m, 3H), 2.87-2.79 (m, 3H), 2.69 (d, J =10.0 Hz, 1H), 2.22 (d, J = 12.0 Hz, 2H), 2.13 (s, 3H), 1.94-1.67 (m, 8H)[α]_(D) ²⁰ +11.8 (c 0.13, CHCl₃) 99% ee; absolute stereochemistryunknown Enantiomer of Ex. 33 (+)-8-[(1R*,3R*)-3-hydroxycyclohexyl]-6-methyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 33 (A)

436 ¹H NMR (400 MHz, CDCl₃) δ = 8.34 (s, 1H), 7.30 (d, J = 1.0 Hz, 1H),5.97 (br s, 1H), 5.35 (br s, 1H), 4.35 (br s, 1H), 3.96 (br s, 1H), 3.81(dd, J = 5.9, 10.2 Hz, 2H), 3.01-2.87 (m, 3H), 2.86-2.79 (m, 3H),2.75-2.61 (m, 1H), 2.22 (d, J = 12.8 Hz, 2H), 2.13 (s, 3H), 1.91-1.65(m, 8H) [α]_(D) ²⁰ −17.8 (c 0.13, CHCl₃) >99% ee; absolutestereochemistry unknown Enantiomer of Ex. 32(−)-8-[(1R*,3R*)-3-hydroxycyclohexyl]- 6-methyl-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one34 (D)

478 [M + Na]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65- 8.52 (m, 1H),8.11-7.97 (m, 2H), 6.18- 5.67 (m, 1H), 4.52 (br s, 1H), 4.12 (br s, 1H),3.82 (br s, 1H), 3.59 (br s, 2H), 3.00-2.76 (m, 6H), 2.26-1.89 (m, 2H),1.85-1.32 (m, 9H) [α]_(D) ²⁰ +4.3 (c 0.2, DMSO) >99% ee; absolutestereochemistry unknown. Enantiomer of Ex. 35(+)-6-chloro-8-[(1R*,3R*)-3- hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one35 (D)

478 [M + Na]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ = 8.62- 8.54 (m, 1H),8.10-7.92 (m, 2H), 6.16- 5.65 (m, 1H), 4.51 (br s, 1H), 4.13 (br s, 1H),3.83 (br s, 1H), 3.60 (br s, 2H), 2.95-2.74 (m, 6H), 2.20-1.89 (m, 2H),1.89-1.36 (m, 9H) [α]_(D) ²⁰ −8.7 (c 0.2, DMSO) 93% ee; absolutestereochemistry unknown. Enantiomer of Ex. 34(−)-6-chloro-8-[(1R*,3R*)-3- hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one36 (A)

406 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H),6.34 (d, J = 9.3 Hz, 1H), 6.01-5.86 (m, 1H), 4.10- 3.95 (m, 1H), 3.79(d, J = 10.5 Hz, 2H), 2.93 (br s, 2H), 2.83 (s, 3H), 2.79-2.51 (m, 1H),2.34 (br s, 1H), 2.19 (d, J = 12.3 Hz, 2H), 2.10-1.99 (m, 1H), 1.89 (dd,J = 7.7, 18.7 Hz, 4H), 1.76-1.61 (m, 2H), 1.60-1.45 (m, 1H), 0.78 (d, J= 7.0 Hz, 3H) 95% ee; Single enantiomer, absolute stereochemistry known.8-[(1R,2S)-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 37 (A)

420 ¹H NMR (400 MHz, CDCl₃) δ = 8.34 (s, 1H), 7.30 (s, 1H), 6.04-5.91(m, 1H), 4.08-3.95 (m, 1H), 3.85-3.72 (m, 2H), 3.01-2.88 (m, 2H), 2.83(s, 3H), 2.41- 2.28 (m, 1H), 2.24-2.16 (m, 2H), 2.14 (s, 3H), 2.10-2.02(m, 1H), 2.00-1.80 (m, 3H), 1.73 (br s, 4H), 1.63-1.53 (m, 1H), 0.76 (d,J = 7.0 Hz, 3H); 96% ee; Single enantiomer, absolute stereochemistryknown. 6-methyl-8-[(1R,2S)-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one38 (D)

440 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.65 (s, 1H), 5.99 (d, J =7.3 Hz, 1H), 4.10-3.93 (m, 1H), 3.79 (d, J = 8.8 Hz, 2H), 2.92 (br s,2H), 2.83 (s, 3H), 2.41-2.27 (m, 1H), 2.18 (d, J = 12.0 Hz, 2H),2.11-2.02 (m, 1H), 2.00-1.76 (m, 4H), 1.74-1.63 (m, 2H), 1.61-1.48 (m,1H), 0.77 (d, J = 7.0 Hz, 3H); 96% ee; Single enantiomer, absolutestereochemistry known. Enantiomer of Ex. 39 6-chloro-8-[(1R,2S)-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 39 (D)

462 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.65 (s, 1H),6.00 (dt, J = 7.0, 9.8 Hz, 1H), 4.02 (td, J = 2.1, 4.1 Hz, 1H),3.88-3.72 (m, 2H), 3.01-2.90 (m, 2H), 2.83 (s, 3H), 2.35 (tt, J = 7.0,10.4 Hz, 1H), 2.24-2.16 (m, 2H), 2.12-2.03 (m, 1H), 2.01-1.82 (m, 3H),1.77-1.61 (m, 3H), 1.59-1.48 (m, 1H), 0.78 (d, J = 7.0 Hz, 3H); 97% ee;Single enantiomer, absolute stereochemistry known. Enantiomer of Ex. 386-chloro-8-[(1S,2R)-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one40 (A)

450 ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.38 (s, 1H), 6.06-5.92(m, 1H), 4.10-3.97 (m, 1H), 3.90-3.72 (m, 4H), 3.03-2.89 (m, 2H),2.86-2.75 (m, 5H), 2.42-2.29 (m, 1H), 2.25-2.15 (m, 2H), 2.12-2.01 (m,1H), 2.01-1.81 (m, 3H), 1.79-1.48 (m, 4H), 0.77 (d, J = 7.0 Hz, 3H); 95%ee; Single enantiomer, absolute stereochemistry known. Enantiomer of Ex.41 6-(2-hydroxyethyl)-8-[(1R,2S)-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one41 (A)

450 ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.38 (s, 1H), 6.04-5.94(m, 1H), 4.08-3.98 (m, 1H), 3.91-3.74 (m, 4H), 3.02-2.89 (m, 3H),2.86-2.78 (m, 5H), 2.42-2.29 (m, 1H), 2.25-2.15 (m, 2H), 2.11-2.01 (m,1H), 2.01-1.80 (m, 3H), 1.70-1.63 (m, 2H), 1.62-1.49 (m, 1H), 0.77 (d, J= 7.0 Hz, 3H); >99% ee ; Single enantiomer, absolute stereochemistryknown. Enantiomer of Ex. 40 6-(2-hydroxyethyl)-8-[(1S,2R)-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 42 (A)

435 ¹H NMR (400 MHz, CDCl₃) δ = 8.45- 8.24 (m, 1H), 7.29 (s, 1H),6.03-5.93 (m, 1H), 5.38-5.11 (m, 1H), 4.22-4.10 (m, 1H), 4.08-3.94 (m,1H), 3.78-3.67 (m, 2H), 3.10-2.95 (m, 2H), 2.76 (d, J = 5.5 Hz, 3H),2.41-2.27 (m, 1H), 2.20-2.13 (m, 4H), 2.10-2.01 (m, 1H), 2.00-1.79 (m,3H), 1.73-1.59 (m, 5H), 0.76 (d, J = 7.0 Hz, 3H); 96% ee; Singleenantiomer, absolute stereochemistry known. Enantiomer of Ex. 43N-methyl-4-({6-methyl-8-[(1R,2S)-2- methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)piperidine-1-sulfonamide 43(A)

435 ¹H NMR (400 MHz, CDCl₃) δ = 8.34 (s, 1H), 7.30 (d, J = 0.8 Hz, 1H),6.01-5.93 (m, 1H), 4.20 (d, J = 5.0 Hz, 1H), 4.07- 3.96 (m, 1H), 3.72(dd, J = 2.8, 12.3 Hz, 2H), 3.08-2.97 (m, 2H), 2.76 (d, J = 5.3 Hz, 3H),2.39-2.28 (m, 1H), 2.17 (d, J = 3.8 Hz, 1H), 2.14 (s, 3H), 2.10-2.01 (m,1H), 1.99-1.81 (m, 3H), 1.73-1.56 (m, 5H), 0.76 (d, J = 7.0, 3H); 96%ee; Single enantiomer, absolute stereochemistry known. Enantiomer of Ex.42 N-methyl-4-({6-methyl-8-[(1S,2R)-2- methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)piperidine-1-sulfonamide 44(A)

421 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H),6.34 (d, J = 9.3 Hz, 1H), 6.00-5.87 (m, 1H), 4.40- 4.29 (m, 1H),4.08-3.96 (m, 1H), 3.78- 3.65 (m, 2H), 3.02 (br s, 2H), 2.75 (d, J = 5.3Hz, 3H), 2.40-2.29 (m, 1H), 2.20- 2.11 (m, 2H), 2.10-2.00 (m, 1H), 1.89(d, J = 9.8 Hz, 3H), 1.75-1.55 (m, 4H), 0.78 (d, J = 7.0 Hz, 3H); >99%ee; Single enantiomer, absolute stereochemistry known. Enantiomer of Ex.45 N-methyl-4-({8-[(1R,2S)-2- methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)piperidine-1-sulfonamide 45(A)

421 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H),6.34 (d, J = 9.3 Hz, 1H), 5.93 (dt, J = 7.5, 9.8 Hz, 1H), 4.24 (q, J =4.9 Hz, 1H), 4.10-3.96 (m, 1H), 3.78-3.68 (m, 2H), 3.08-2.98 (m, 2H),2.76 (d, J = 5.3 Hz, 3H), 2.41- 2.28 (m, 1H), 2.20-2.11 (m, 2H), 2.09-1.98 (m, 1H), 1.96-1.82 (m, 3H), 1.73- 1.61 (m, 4H), 0.78 (d, J = 7.0Hz, 3H); 97% ee; Single enantiomer, absolute stereochemistry known.Enantiomer of Ex. 44 N-methyl-4-({8-[(1S,2R)-2-methylcyclopentyl]-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)piperidine-1-sulfonamide 46 (A)

487 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.38 (s, 1H),6.07-5.91 (m, 1H), 5.69-5.30 (m, 1H), 4.47-4.26 (m, 1H), 4.12-3.96 (m,1H), 3.85 (br s, 2H), 3.78- 3.63 (m, 2H), 3.12-2.92 (m, 3H), 2.81 (s,2H), 2.76 (d, J = 5.3 Hz, 3H), 2.71-2.59 (m, 1H), 2.43-2.28 (m, 1H),2.21-2.13 (m, 2H), 2.11-2.00 (m, 1H), 2.00-1.81 (m, 3H), 1.70-1.48 (m,3H), 0.77 (d, J = 7.0 Hz, 3H); >99% ee; Single enantiomer, absolutestereochemistry known. 4-({6-(2-hydroxyethyl)-8-[(1S,2R)-2- Enantiomerof Ex. 4 methylcyclopentyl]-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-methylpiperidine-1- sulfonamide 47 (F)

463 ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.56 (s, 1H), 6.74 (br s,1H), 5.95- 6.09 (m, 1H), 5.31 (s, 2H), 4.04 (br s, 1H), 3.70-3.89 (m,2H), 3.36-3.56 (m, 2H), 2.95 (br s, 2H), 2.84 (s, 3H), 2.67 (br s, 1H),2.30-2.44 (m, 1H), 2.20 (d, J = 10.3 Hz, 2H), 2.01-2.13 (m, 1H),1.83-1.98 (m, 3H), 1.72 (d, J = 11.5 Hz, 2H), 1.51-1.62 (m, 1H), 0.76ppm (d, J = 7.0 Hz, 3H); 96% ee; Single enantiomer, absolutestereochemistry known. 2-(8-[(1R,2S)-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetamide 48 (A)

472 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.53 (s, 1H),5.97 (dt, J = 7.5, 9.8 Hz, 1H), 4.39 (d, J = 1.3 Hz, 2H), 4.08- 3.97 (m,1H), 3.84-3.72 (m, 2H), 3.50 (s, 3H), 3.00-2.87 (m, 2H), 2.83 (s, 3H),2.39-2.28 (m, 1H), 2.25-2.15 (m, 2H), 2.09-1.99 (m, 1H), 1.99-1.82 (m,3H), 1.74-1.65 (m, 2H), 1.60-1.48 (m, 2H), 0.76 (d, J = 7.3 Hz, 3H); 95%ee; Single enantiomer, absolute stereochemistry known. Enantiomer of Ex.49 6-(methoxymethyl)-8-[(1R,2S)-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one49 (A)

450 ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.54 (s, 1H), 5.97 (td, J= 9.8, 7.5 Hz, 1H), 5.31 (br s,, 1H), 4.40 (d, J = 1.3 Hz, 2H), 4.04 (d,J = 6.8 Hz, 1H), 3.80 (d, J = 10.8 Hz, 2H), 3.50 (s, 3H), 2.88-3.03 (m,2H), 2.84 (s, 3H), 2.68 (d, J = 16.1 Hz, 1H), 2.35 (tquin, J = 10.4, 7.1Hz, 1H), 2.21 (d, J = 12.5 Hz, 2H), 2.02-2.12 (m, 1H), 1.80-1.99 (m,3H), 1.67-1.77 (m, 2H), 1.49-1.61 (m, 1H), 0.77 ppm (d, J = 7.0 Hz, 3H);97% ee; Single enantiomer, absolute 6-(methoxymethyl)-8-[(1S,2R)-2-stereochemistry known. methylcyclopentyl]-2-{[1- Enantiomer of Ex. 48(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one50 (A)

458 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.45 (s, 1H),5.97 (dt, J = 7.3, 9.8 Hz, 1H), 4.56 (br s, 2H), 4.04 (dt, J = 1.6, 3.2Hz, 1H), 3.86-3.71 (m, 2H), 3.19- 3.06 (m, 1H), 3.01-2.88 (m, 2H), 2.83(s, 3H), 2.36 (ddd, J = 3.0, 7.2, 10.1 Hz, 1H), 2.24-2.15 (m, 2H),2.10-1.99 (m, 1H), 1.98-1.81 (m, 3H), 1.77-1.67 (m, 2H), 1.61-1.48 (m,2H), 0.77 (d, J = 7.0 Hz, 3H); 97% ee; Single enantiomer, absolutestereochemistry known. 6-(hydroxymethyl)-8-[(1R,2S)-2- Enantiomer of Ex.51 methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 51 (A)

458 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.45 (s, 1H),6.01-5.93 (m, 1H), 4.56 (s, 2H), 4.09-3.98 (m, 1H), 3.86- 3.72 (m, 2H),3.19-3.04 (m, 1H), 3.01- 2.87 (m, 1H), 2.83 (s, 3H), 2.40-2.27 (m, 1H),2.24-2.15 (m, 2H), 2.12-1.99 (m, 1H), 1.98-1.82 (m, 3H), 1.79-1.63 (m,4H), 1.58-1.51 (m, 1H), 0.77 (d, J = 7.0 Hz, 3H); 97% ee; Singleenantiomer, absolute stereochemistry known. Enantiomer of Ex. 506-(hydroxymethyl)-8-[(1S,2R)-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one52 (A)

472 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.41 (d, J = 9.3Hz, 1H), 6.35 (d, J = 9.3 Hz, 1H), 6.05-5.87 (m, 1H), 5.38 (br s, 1H),4.04 (br s, 1H), 3.86-3.71 (m, 4H), 3.39 (s, 3H), 3.23 (t, J = 5.8 Hz,2H), 3.10-2.96 (m, 2H), 2.69 (br s,, 1H), 2.45-2.26 (m, 1H), 2.21-2.10(d, J = 12.8 Hz, 2H), 2.08-1.97 (m, 1H), 1.95-1.79 (m, 3H), 1.64-1.47(m, 3H), 0.79 (d, J = 7.0 Hz, 3H); >99% ee; Single enantiomer, absolutestereochemistry known 2-({1-[(2- methoxyethyl)sulfonyl]piperidin-4-yl}amino)-8-[(1R,2S)-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one 53 (A)

408 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.59 (br s, 1H), 7.90-7.69 (m, 1H),7.67 (d, J = 9.3 Hz, 1H), 6.21 (d, J = 7.8 Hz, 1H), 6.11 (br s, 1H),4.63-4.46 (m, 1H), 4.42 (br s, 1H), 4.08-3.79 (m, 1H), 3.60-3.53 (m,2H), 2.88 (s, 3H), 2.87-2.81 (m, 2H), 2.20 (br s, 2H), 2.06-1.83 (m,4H), 1.70- 1.52 (m, 4H); [α]_(D) ²² +15.0 (c 0.1, MeOH) >99% ee Absolutestereochemistry unknown. Enantiomer of Ex. 54(+)-8-[(1R*,3R*)-3-hydroxycyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 54 (A)

408 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.59 (br s, 1H), 7.91-7.69 (m, 1H),7.67 (d, J = 9.3 Hz, 1H), 6.21 (d, J = 7.3 Hz, 1H), 6.11 (br s, 1H),4.62-4.47 (m, 1H), 4.42 (br s, 1H), 4.13-3.80 (m, 1H), 3.60-3.53 (m,2H), 2.88 (s, 3H), 2.87-2.82 (m, 2H), 2.20 (br s, 2H), 2.06-1.83 (m,4H), 1.69- 1.53 (m, 4H); [α]_(D) ²² −16.1 (c 0.1, MeOH) >99% ee;absolute stereochemistry unknown. Enantiomer of Ex. 53(−)-8-[(1R*,3R*)-3-hydroxycyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 55 (A)

459.0 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.37 (s, 1H), 7.33 (d, J =1.3 Hz, 1H), 5.84-5.68 (m, 1H), 5.00 (m, 1H), 4.09 (m, 1H), 4.00 (br s,1H), 3.73 (d, J = 12.3 Hz, 2H), 3.03 (t, J = 11.7 Hz, 2H), 2.76 (d, J =5.2, 3H), 2.42-2.26 (m, 2H), 2.15 (d, J = 1.3 Hz, 5H), 2.08-1.96 (m,2H), 1.90 (dd, J = 6.1, 12.7 Hz, 1H), 1.77-1.63 (m, 3H); 98% ee; Singleenantiomer, absolute stereochemistry known.4-({8-[(1R,2R)-2-hydroxycyclopentyl]-6-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl}amino)-N-methylpiperidine-1-sulfonamide 56 (A)

459 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.45 (d, J = 9.3Hz, 1H), 6.34 (d, J = 9.0 Hz, 1H), 5.67 (br s, 2H), 4.77- 4.35 (m, 1H),4.03 (d, J = 6.0 Hz, 1H), 3.75 (d, J = 11.5 Hz, 2H), 3.03 (t, J = 10.8Hz, 2H), 2.93-2.79 (m, 1H), 2.75 (d, J = 5.3 Hz, 3H), 2.28-2.09 (m, 3H),2.06- 1.80 (m, 4H), 1.72-1.58 (m, 3H), 1.17 (s, 3H); [α]_(D) ²² −13.0 (c0.20, CHCl₃) >99% ee; absolute stereochemistry unknown.(−)-4-({8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 57methylcyclopentyl]-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-methylpiperidine-1- sulfonamide 57 (A)

459 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.45 (d, J = 9.3Hz, 1H), 6.35 (d, J = 9.5 Hz, 1H), 5.71 (br s, 1H), 5.51 (br s, 1H),4.26 (br s, 1H), 4.01 (br s, 1H), 3.65-3.83 (m, 2H), 2.97-3.13 (m, 2H),2.78-2.95 (m, 1H), 2.76 (d, J = 5.5 Hz, 3H), 2.11-2.29 (m, 3H),1.80-2.08 (m, 4H), 1.62-1.74 (m, 3H), 1.17 ppm (s, 3H); [α]_(D) ²² +8.6(c 0.17, CHCl₃) >99% ee; absolute stereochemistry unknown.(+)-4-({8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 56methylcyclopentyl]-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-methylpiperidine-1- sulfonamide 58 (A)

462 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.46 (d, J = 9.3Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 5.82-5.66 (m, 1H), 5.49 (br s, 1H),5.14 (d, J = 48 Hz, 2H), 4.05 (br s, 1H), 3.97-3.86 (m, 2H), 3.26-3.11(m, 2H), 2.83 (br s, 1H), 2.30-2.16 (m, 3H), 2.07-1.97 (m, 2H),1.95-1.80 (m, 2H), 1.67 (br s, 2H), 1.17 (s, 3H) ¹⁹F NMR (377 MHz,DMSO-d₆) δ = −215.3 (s, 1F) [α]_(D) ²² −18.7 (c 0.5, CHCl₃) [α]_(D) ²²−30.1 (c 0.5, MeOH) (−)-2-({1- 99% ee; absolute stereochemistry[(fluoromethyl)sulfonyl]piperidin-4- unknown.yl}amino)-8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 59methylcyclopentyl]pyrido[2,3- d]pyrimidin-7(8H)-one 59 (A)

462 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.45 (d, J = 9.3Hz, 1H), 6.36 (d, J = 9.3 Hz, 1H), 5.73 (br s, 1H), 5.40 (br s, 1H),5.26-5.02 (m, 2H), 4.07 (br s, 1H), 3.93 (t, J = 11.9 Hz, 2H), 3.27-3.11(m, 2H), 2.93-2.73 (m, 1H), 2.30-2.18 (m, 3H), 2.06-1.98 (m, 2H),1.96-1.79 (m, 2H), 1.71-1.61 (m, 2H), 1.18 (s, 3H) ¹⁹F NMR (377 MHz,DMSO-d₆) δ = −215.3 (s, 1F) [α]_(D) ²² +33.3 (c 0.5, MeOH) 99% ee;absolute stereochemistry (+)-2-({1- unknown[(fluoromethyl)sulfonyl]piperidin-4- Enantiomer of Ex. 58yl}amino)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one 60 (A)

531 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.45 (d, J = 9.3Hz, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.72 (br s, 1H), 5.55- 5.23 (m, 1H),4.64-4.57 (m, 1H), 4.13- 3.89 (m, 1H), 3.78-3.68 (m, 2H), 3.20 (s, 3H),3.03 (d, J = 5.8 Hz, 4H), 2.94-2.77 (m, 1H), 2.68-2.36 (m, 1H), 2.17 (d,J = 13.3 Hz, 3H), 2.04-1.82 (m, 4H), 1.66 (d, J = 10.5 Hz, 2H), 1.22 (s,6H), 1.17 (s, 3H); (−)-4-({8-[(1R*,2R*)-2-hydroxy-2- [α]_(D) ²⁰ −13.3 (c0.27, MeOH) methylcyclopentyl]-7-oxo-7,8- 98% ee; absolutestereochemistry dihydropyrido[2,3-d]pyrimidin-2- unknown.yl}amino)-N-(2-methoxy-2- Enantiomer of Ex. 61methylpropyl)piperidine-1-sulfonamide 61 (A)

531 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.45 (d, J = 9.3Hz, 1H), 6.35 (d, J = 9.5 Hz, 1H), 5.72 (br s, 1H), 5.55- 5.26 (m, 1H),4.61 (t, J = 5.6 Hz, 1H), 4.00 (br s, 1H), 3.74 (d, J = 11.8 Hz, 2H),3.20 (s, 3H), 3.05-2.96 (m, 4H), 2.86 (br s, 1H), 2.70-2.30 (m, 1H),2.25-2.13 (m, 3H), 2.04-1.83 (m, 4H), 1.67-1.61 (m, 2H), 1.22 (s, 6H),1.17 (s, 3H); [α]_(D) ²⁰ +13.8 (c 0.27, MeOH)(+)-4-({8-[(1R*,2R*)-2-hydroxy-2- >99% ee; absolute stereochemistrymethylcyclopentyl]-7-oxo-7,8- unknown. dihydropyrido[2,3-d]pyrimidin-2-Enantiomer of Ex. 60 yl}amino)-N-(2-methoxy-2-methylpropyl)piperidine-1-sulfonamide 62 (A)

529 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.55 (br s, 1H), 7.71 (d, J =9.3 Hz, 1H), 6.28 (d, J = 9.3 Hz, 1H), 6.12-5.95 (m, 1H), 4.15- 3.97 (m,2H), 3.89 (m, 1H), 3.81-3.75 (m, 1H), 3.69 (m, 2H), 3.09 (m, 2H),3.04-2.93 (m, 2H), 2.67-2.54 (m, 1H), 2.42-2.28 (m, 1H), 2.26-2.03 (m,4H), 2.02-1.88 (m, 4H), 1.84-1.77 (m, 2H), 1.69-1.59 (m, 2H), 1.12 (s,3H); [α]_(D) ²⁰ −10.8 (c 0.12, MeOH)(−)-4-({8-[(1R*,2R*)-2-hydroxy-2- >99% de; Single diastereomer.methylcyclopentyl]-7-oxo-7,8- Absolute stereochemistry known (S) atdihydropyrido[2,3-d]pyrimidin-2- THF center; relative (but not absolute)yl}amino)-N-[(2S)-tetrahydrofuran-2- stereochemistry known at theylmethyl]piperidine-1-sulfonamide cyclopentyl chiral centers. Made from(S)-tetrahydro-furfurylamine and racemic Intermediate 1. 63 (A)

529 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.54 (br s, 1H), 7.71 (d, J =9.3 Hz, 1H), 6.37-6.24 (m, 1H), 6.07 (br s, 1H), 4.14-3.98 (m, 2H), 3.89(td, J = 6.6, 8.1 Hz, 1H), 3.83- 3.74 (m, 1H), 3.69 (br d, J = 11.0 Hz,2H), 3.15-3.04 (m, 2H), 2.99 (br s, 2H), 2.68-2.52 (m, 1H), 2.35 (br d,J = 11.5 Hz, 1H), 2.27-2.02 (m, 4H), 2.02-1.86 (m, 4H), 1.83-1.71 (m,2H), 1.69-1.51 (m, 2H), 1.12 (s, 3H); (+)-4-({8-[(1R*,2R*)-2-hydroxy-2-[α]_(D) ²⁰ +10 (c 0.12, MeOH) methylcyclopentyl]-7-oxo-7,8- >99% de;Single diastereomer. dihydropyrido[2,3-d]pyrimidin-2- Absolutestereochemistry known (S) at yl}amino)-N-[(2S)-tetrahydrofuran-2- THFcenter; relative (but not absolute) ylmethyl]piperidine-1-sulfonamidestereochemistry known at the cyclopentyl chiral centers. Made from(S)-tetrahydro-furfurylamine and racemic Intermediate 1. 64 (A)

529 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.54 (s, 1H), 7.69 (d, J = 9.3Hz, 1H), 6.27 (d, J = 9.2 Hz, 1H), 6.04 (s, 1H), 4.12-3.97 (m, 2H),3.91-3.83 (m, 1H), 3.79-3.63 (m, 3H), 3.12-2.92 (m, 4H), 2.59 (s, 1H),2.33 (s, 1H), 2.25-1.85 (m, 8H), 1.81- 1.74 (m, 1H), 1.73-1.54 (m, 3H),1.10 (s, 3H); [α]_(D) ²⁰ −13.9 (c 0.13, MeOH) >99% de; Singlediastereomer. (−)-4-({8-[(1R*,2R*)-2-hydroxy-2- Absolute stereochemistryknown (R) at methylcyclopentyl]-7-oxo-7,8- THF center; relative (but notabsolute) dihydropyrido[2,3-d]pyrimidin-2- stereochemistry known at theyl}amino)-N-[(2R)-tetrahydrofuran-2- cyclopentyl chiral centers.ylmethyl]piperidine-1-sulfonamide . Made from(R)-tetrahydro-furfurylamine and racemic Intermediate 1. 65 (A)

529 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.53 (s, 1H), 7.69 (d, J = 9.3Hz, 1H), 6.26 (d, J = 9.3 Hz, 1H), 6.05 (br s, 1H), 4.14- 3.96 (m, 2H),3.92-3.83 (m, 1H), 3.79- 3.62 (m, 3H), 3.13-2.91 (m, 4H), 2.59 (s, 1H),2.40-2.26 (m, 1H), 2.23-1.88 (m, 8H), 1.81-1.56 (m, 4H), 1.10 (s, 3H);[α]_(D) ²⁰ +8.4 (c 0.10, MeOH) >99% de; Single diastereomer. Absolutestereochemistry known (R) at (+)-4-({8-[(1R*,2R*)-2-hydroxy-2- THFcenter; relative (but not absolute) methylcyclopentyl]-7-oxo-7,8-stereochemistry known at the dihydropyrido[2,3-d]pyrimidin-2-cyclopentyl chiral centers. yl}amino)-N-[(2R)-tetrahydrofuran-2- Madefrom (R)-tetrahydro-furfurylamine ylmethyl]piperidine-1-sulfonamide andracemic Intermediate 1. 66 (A)

523 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.57 (br s, 1H), 7.71 (d, J =9.0 Hz, 1H), 6.28 (d, J = 9.0 Hz, 1H), 6.07 (br s, 1H), 4.08 (br s, 1H),3.74-3.65 (m, 2H), 3.39 (t, J = 13.1 Hz, 2H), 3.00 (br s, 2H), 2.61 (brs, 1H), 2.35 (q, J = 10.5 Hz, 1H), 2.28- 2.06 (m, 3H), 2.00 (br s, 2H),1.80 (d, J = 12.5 Hz, 1H), 1.67 (t, J = 18.8 Hz, 5H), 1.12 (s, 3H); ¹⁹FNMR (377 MHz, DMSO-d₆) δ = −94.4 to −94.6 (m, 2F) [α]_(D) ²⁰ −11.3 (c0.15, MeOH) >99% ee; absolute stereochemistry(−)-N-(2,2-difluoropropyl)-4-({8- unknown. [(1R*,2R*)-2-hydroxy-2-Enantiomer of Ex. 67 methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)piperidine-1-sulfonamide 67(A)

523 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.53 (br s, 1H), 7.69 (d, J =9.2 Hz, 1H), 6.27 (d, J = 9.5 Hz, 1H), 6.11-5.89 (m, 1H), 4.15- 3.96 (m,1H), 3.74-3.65 (m, 2H), 3.41- 3.34 (m, 2H), 3.02-2.92 (m, 2H), 2.65-2.56 (m, 1H), 2.33 (q, J = 10.3 Hz, 1H), 2.23-2.04 (m, 3H), 1.99-1.91(m, 2H), 1.78 (d, J = 12.8 Hz, 1H), 1.69-1.58 (m, 5H), 1.10 (s, 3H) ¹⁹FNMR (377 MHz, DMSO-d₆) δ = −94.4 to −94.6 (m, 2F) [α]_(D) ²⁰ +8.4 (c0.13, MeOH) 99% ee; absolute stereochemistry(+)-N-(2,2-difluoropropyl)-4-({8- unknown. [(1R*,2R*)-2-hydroxy-2-Enantiomer of Ex. 66 methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)piperidine-1-sulfonamide 68(A)

529 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.45 (d, J = 9.3Hz, 1H), 6.39-6.31 (m, 1H), 5.77-5.48 (m, 2H), 4.48-4.36 (m, 1H), 3.98(d, J = 11.3 Hz, 3H), 3.74 (d, J = 12.3 Hz, 2H), 3.50-3.37 (m, 3H), 2.99(br s, 3H), 2.59-2.30 (m, 1H), 2.27- 2.11 (m, 3H), 2.06-1.95 (m, 4H),1.94- 1.81 (m, 2H), 1.73-1.65 (m, 2H), 1.60- 1.51 (m, 2H), 1.17 (s, 3H);[α]_(D) ²⁰ −12.7 (c 0.44, MeOH) 99% ee; absolute stereochemistryunknown. (−)-4-({8-[(1R*,2R*)-hydroxy-2- Enantiomer of Ex. 69methylcyclopentyl]-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-(tetrahydro-2H-pyran-4- yl)piperidine-1-sulfonamide 69 (A)

529 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.45 (d, J = 9.3Hz, 1H), 6.35 (d, J = 9.8 Hz, 1H), 5.81-5.65 (m, 1H), 5.60- 5.40 (m,1H), 4.39-4.24 (m, 1H), 3.98 (d, J = 11.5 Hz, 3H), 3.73 (br s, 2H),3.51-3.39 (m, 3H), 2.98 (br s, 3H), 2.57- 2.31 (m, 1H), 2.29-2.13 (m,3H), 1.99 (d, J = 10.3 Hz, 4H), 1.94-1.80 (m, 2H), 1.76-1.64 (m, 2H),1.56 (dd, J = 4.3, 12.8 Hz, 2H), 1.17 (s, 3H); [α]_(D) ²⁰ +12.8 (c 0.25,MeOH) 99% ee; absolute stereochemistry (+)-4-({8-[(1R*,2R*)-hydroxy-2-unknown. methylcyclopentyl]-7-oxo-7,8- Enantiomer of Ex. 68dihydropyrido[2,3-d]pyrimidin-2- yl}amino)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-sulfonamide 70 (A)

526 ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.54-7.41 (m, 1H), 6.36(d, J = 9.3 Hz, 1H), 5.73 (br s, 1H), 5.46 (br s, 1H), 4.05 (br s, 1H),3.94-3.79 (m, 3H), 3.48- 3.26 (m, 3H), 3.22-3.03 (m, 3H), 2.82 (br s,1H), 2.66-2.52 (m, 2H), 2.31-2.17 (m, 3H), 2.06-1.78 (m, 4H), 1.65-1.56(m, 3H), 1.17 (s, 3H); [α]_(D) ²⁰ −32.0 (c 0.2, CHCl₃) >99% de; Singlediasteromer, absolute stereochemistry known (R,R) at the cyclopentylchiral centers, but unknown at sulfolane center. Made from(±)-tetrahydro-3- 2-[(1-{[(3ξ)-1,1- thiophenesulfonyl chloride1,1-dioxide dioxidotetrahydrothiophen-3- and single enantiomerintermediate 2B yl]sulfonyl}piperidin-4-yl)amino]-8- from Ex. 2[(1R,2R)-2-hydroxy-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one - Isomer (A) 71 (A)

526 ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.46 (d, J = 9.3 Hz, 1H),6.36 (d, J = 9.3 Hz, 1H), 5.73 (t, J = 7.8 Hz, 1H), 5.46 (br s, 1H),4.05 (br s, 1H), 3.94- 3.81 (m, 3H), 3.45-3.29 (m, 3H), 3.21- 3.08 (m,3H), 2.82 (br s, 1H), 2.66-2.51 (m, 2H), 2.30-2.17 (m, 3H), 2.05-1.80(m, 4H), 1.65-1.57 (m, 3H), 1.17(s, 3H); [α]_(D) ²⁰ −1.3 (c 0.2,CHCl₃) >99% de; Single diasteromer, absolute stereochemistry known (R,R)at the cyclopentyl chiral centers, but unknown at sulfolane center. Madefrom (±)-tetrahydro-3- 2-[(1-{[(3ξ)-1,1- thiophenesulfonyl chloride1,1-dioxide dioxidotetrahydrothiophen-3- and single-enantiomerintermediate 2B yl]sulfonyl}piperidin-4-yl)amino]-8- from Ex. 2[(1R,2R)-2-hydroxy-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one - Isomer B 72 (A)

488 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.45 (d, J = 9.3Hz, 1H), 6.35 (d, J = 9.3 Hz, 1H), 5.71 (t, J = 8.3 Hz, 1H), 5.44 (br s,1H), 3.99 (br s, 1H), 3.82- 3.74 (m, 4H), 3.40 (s, 3H), 3.22 (t, J = 5.8Hz, 2H), 3.06-2.97 (m, 2H), 2.89 (d, J = 8.8 Hz, 1H), 2.61-2.35 (m, 1H),2.28- 2.12 (m, 3H), 2.05-1.96 (m, 2H), 1.94- 1.81 (m, 2H), 1.72-1.61 (m,2H), 1.17 (s, 3H); [α]_(D) ²⁰ −14.5 (c 0.17, MeOH) 95% ee; absolutestereochemistry (−)-8-[(1R*,2R*)-2-hydroxy-2- unknown.methylcyclopentyl]-2-({1-[(2- Enantiomer of Ex. 73methoxyethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 73 (A)

488 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.45 (d, J = 9.3Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 5.72 (t, J = 8.5 Hz, 1H), 5.48 (br s,1H), 3.98 (br s, 1H), 3.86- 3.69 (m, 4H), 3.40 (s, 3H), 3.23 (t, J = 5.9Hz, 2H), 3.08-2.96 (m, 2H), 2.88 (br s, 1H), 2.62-2.38 (m, 1H),2.30-2.11 (m, 3H), 2.06-1.95 (m, 2H), 1.95-1.79 (m, 2H), 1.64-1.56 (m,2H), 1.17 (s, 3H); [α]_(D) ²⁰ +14.2 (c 0.15, MeOH) 99% ee; absolutestereochemistry unknown. (+)-8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex.72 methylcyclopentyl]-2-({1-[(2- methoxyethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 74 (A)

470 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.54 (s, 1H), 7.69 (d, J = 9.6Hz, 1H), 6.27 (d, J = 9.2 Hz, 1H), 6.06 (s, 1H), 4.16-4.04 (m, 1H),3.83-3.70 (m, 2H), 3.17-3.04 (m, 2H), 2.64-2.46 (m, 2H), 2.40-1.88 (m,6H), 1.82-1.55 (m, 3H), 1.11(s, 3H), 1.09-1.02 (m, 4H); [α]_(D) ²⁰ −14.2(c 0.12, MeOH) >99% ee; absolute stereochemistry unknown. Enantiomer ofEx. 75 (−)-2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one 75 (A)

470 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.54 (s, 1H), 7.69 (d, J = 9.2Hz, 1H), 6.27 (d, J = 9.6 Hz, 1H), 6.14-5.90 (m, 1H), 4.16- 4.03 (m,1H), 3.83-3.69 (m, 2H), 3.18- 3.04 (m, 2H), 2.66-2.44 (m, 2H), 2.37-1.93 (m, 6H), 1.82-1.55 (m, 3H), 1.11 (s, 3H), 1.09-1.02 (m, 4H);[α]_(D) ²⁰ +11.9 (c 0.16, MeOH) 99% ee; absolute stereochemistryunknown. Enantiomer of Ex. 74 (+)-2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one 76 (A)

436 ¹H NMR (400 MHz, CD₃OD) δ = 8.54 (s, 1H), 7.69 (d, J = 9.2 Hz, 1H),6.26 (d, J = 9.2 Hz, 1H), 6.05 (s, 1H), 4.17-4.03 (m, 1H), 3.85-3.69 (m,2H), 3.15-3.00 (m, 4H), 2.64-2.52 (m, 1H), 2.40-1.92 (m, 6H), 1.81-1.52(m, 3H), 1.34 (t, J = 7.6 Hz, 3H), 1.10 (s, 3H); [α]_(D) ²⁰ −16.9 (c0.16, MeOH) >99% ee; absolute stereochemistry unknown. Enantiomer of Ex.77 (−)-2-{[1-(ethylsulfonyl)piperidin-4-yl]amino}-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one 77 (A)

436 ¹H NMR (400 MHz, CD₃OD) δ = 8.54 (s, 1H), 7.69 (d, J = 9.2 Hz, 1H),6.26 (d, J = 9.2 Hz, 1H), 6.13-5.88 (m, 1H), 4.16- 4.02 (m, 1H),3.84-3.69 (m, 2H), 3.16- 2.99 (m, 4H), 2.65-2.50 (m, 1H), 2.39- 1.91 (m,6H), 1.81-1.51 (m, 3H), 1.34 (t, J = 7.6 Hz, 3H), 1.11 (s, 3H); [α]_(D)²⁰ +16.9 (c 0.13, MeOH) 99% ee; absolute stereochemistry unknown.Enantiomer of Ex. 76 (+)-2-{[1-(ethylsulfonyl)piperidin-4-yl]amino}-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one 78 (A)

513 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.53 (br s, 1H), 8.08 (d, J =3.0 Hz, 1H), 8.00 (d, J = 3.2 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 6.26(d, J = 9.2 Hz, 1H), 6.05-5.88 (m, 1H), 4.10-3.97 (m, 1H), 3.87 (br d, J= 12.0 Hz, 2H), 3.01 (t, J = 11.6 Hz, 2H), 2.62-2.49 (m, 1H), 2.37-2.17(m, 2H), 2.15-2.00 (m, 2H), 1.99-1.88 (m, 2H), 1.80-1.53 (m, 3H), 1.09(s, 3H); [α]_(D) ²⁰ −7.5 (c 0.12, MeOH) >99% ee; absolutestereochemistry unknown. Enantiomer of Ex. 79(−)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-2-{[1-(1,3-thiazol-2-ylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 79(A)

513 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.54 (br s, 1H), 8.10 (d, J =3.0 Hz, 1H), 8.01 (d, J = 3.3 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 6.27(d, J = 9.3 Hz, 1H), 6.00 (br s, 1H), 4.04 (br s, 1H), 3.89 (br d, J =12.3 Hz, 2H), 3.02 (br t, J = 12.2 Hz, 2H), 2.63- 2.52 (m, 1H),2.38-2.19 (m, 2H), 2.17- 2.05 (m, 2H), 2.00-1.89 (m, 2H), 1.81- 1.62 (m,3H), 1.09 (s, 3H); [α]_(D) ²⁰ +8.8 (c 0.08, MeOH) >99% ee; absolutestereochemistry unknown. Enantiomer of Ex. 78(+)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-2-{[1-(1,3-thiazol-2-ylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 80(A)

514 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 9.73 (s, 1H), 8.55 (br s, 1H),7.70 (d, J = 9.2 Hz, 1H), 6.28 (d, J = 9.2 Hz, 1H), 6.07-5.93 (m, 1H),4.16-4.05 (m, 1H), 3.95 (br d, J = 12.5 Hz, 2H), 3.16 (t, J = 12.0 Hz,2H), 2.63-2.50 (m, 1H), 2.40-2.26 (m, 2H), 2.16 (m, 1H), 2.11-2.02 (m,1H), 2.02- 1.90 (m, 2H), 1.82-1.59 (m, 3H), 1.10 (s, 3H); [α]_(D) ²⁰−13.3 (c 0.12, MeOH) >99% ee; absolute stereochemistry unknown.Enantiomer of Ex. 81 (−)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(1,3,4- thiadiazol-2-ylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 81 (A)

514 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 9.73 (s, 1H), 8.55 (br s, 1H),7.70 (d, J = 9.3 Hz, 1H), 6.28 (d, J = 9.0 Hz, 1H), 6.02 (br s, 1H),4.10 (br s, 1H), 3.95 (br d, J = 12.3 Hz, 2H), 3.16 (br t, J = 12.0 Hz,2H), 2.57 (br s, 1H), 2.40-2.25 (m, 2H), 2.18-1.91 (m, 4H), 1.83-1.57(m, 3H), 1.10 (s, 3H); [α]_(D) ²⁰ +10 (c 0.11, MeOH) 95% ee; absolutestereochemistry unknown. Enantiomer of Ex. 80(+)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-2-{[1-(1,3,4-thiadiazol-2-ylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 82 (A)

470 [M − H₂O + H]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.54 (s, 1H), 8.16 (s,1H), 7.79 (s, 1H), 7.69 (d, J = 9.5 Hz, 1H), 6.27 (d, J = 9.0 Hz, 1H),6.00 (br s, 1H), 3.99 (s, 3H), 3.96-3.90 (m, 1H), 3.66 (d, J = 12.5 Hz,2H), 2.66- 2.49 (m, 3H), 2.38-2.26 (m, 1H), 2.23 (br s, 1H), 2.19-2.02(m, 2H), 2.00-1.90 (m, 2H), 1.74 (br s, 3H), 1.10 (s, 3H); [α]_(D) ²⁰−6.6 (c 0.21, MeOH) >99% ee; absolute stereochemistry unknown.Enantiomer of Ex. 83 (−)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-({1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 83 (A)

470 [M − H₂O + H]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.54 (s, 1H), 8.16 (s,1H), 7.79 (s, 1H), 7.69 (d, J = 9.5 Hz, 1H), 6.27 (d, J = 9.0 Hz, 1H),6.00 (br s, 1H), 3.99 (s, 3H), 3.97-3.90 (m, 1H), 3.66 (br d, J = 12.5Hz, 2H), 2.66-2.52 (m, 3H), 2.40-2.27 (m, 1H), 2.16-1.80 (m, 5H), 1.74(br s, 3H), 1.10 (s, 3H); [α]_(D) ²⁰ +4.7 (c 0.19, MeOH) 93% ee;absolute stereochemistry unknown. Enantiomer of Ex. 82(+)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-2-({1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 84 (A)

470 [M − H₂O + H]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.53 (s, 1H), 7.81 (d, J= 1.0 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 9.3 Hz, 1H), 6.27 (d, J = 9.0Hz, 1H), 6.00 (br s, 1H), 3.97 (br s, 1H), 3.85-3.71 (m, 5H), 2.80 (t, J= 11.8 Hz, 2H), 2.66-2.50 (m, 1H), 2.39-2.29 (m, 1H), 2.26-1.88 (m, 5H),1.81-1.53 (m, 3H), 1.10 (s, 3H); [α]_(D) ²⁰ −10.8 (c 0.15, MeOH) >99%ee; absolute stereochemistry unknown. Enantiomer of Ex. 85(−)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-2-({1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 85 (A)

470 [M − H₂O + H]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.53 (br s, 1H), 7.82 (d,J = 1.0 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 9.3 Hz, 1H), 6.27 (d, J =9.3 Hz, 1H), 6.00 (br s, 1H), 3.98 (br s, 1H), 3.85-3.70 (m, 5H), 2.79(t, J = 11.5 Hz, 2H), 2.65-2.51 (m, 1H), 2.37-2.27 (m, 1H), 2.24-1.91(m, 5H), 1.80-1.55 (m, 3H), 1.10 (s, 3H); [α]_(D) ²⁰ +6.0 (c 0.17, MeOH)99% ee; absolute stereochemistry unknown. Enantiomer of Ex. 84(+)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-2-({1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 86 (A)

512 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.56 (br s, 1H), 7.71 (d, J =9.3 Hz, 1H), 6.29 (d, J = 9.3 Hz, 1H), 6.07 (br s, 1H), 4.21- 4.05 (m,3H), 3.84 (t, J = 11.2 Hz, 2H), 3.13 (t, J = 11.7 Hz, 2H), 2.60 (br s,1H), 2.41-2.18 (m, 2H), 2.14 (d, J = 13.6 Hz, 2H), 2.00 (br s, 2H), 1.80(d, J = 13.1 Hz, 1H), 1.68 (br s, 2H), 1.12 (s, 3H) ¹⁹F NMR (377 MHz,DMSO-d₆) δ = −60.1 to −60.3 (m, 3F) [α]_(D) ²⁰ −18.3 (c 0.12, MeOH) 99%ee; absolute stereochemistry (−)-8-[(1R*,2R*)-2-hydroxy-2- unknown.methylcyclopentyl]-2-({1-[(2,2,2- Enantiomer of Ex. 87trifluoroethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 87 (A)

512 [M + Na]⁺ ¹H NMR (400 MHz, CD₃OD) δ = 8.56 (br s, 1H), 7.71 (d, J =9.3 Hz, 1H), 6.29 (d, J = 9.3 Hz, 1H), 6.06 (br s, 1H), 4.17 (q, J = 9.7Hz, 3H), 3.84 (br t, J = 11.2 Hz, 2H), 3.13 (br t, J = 11.2 Hz, 2H),2.60 (br s, 1H), 2.41-2.19 (m, 2H), 2.16-1.92 (m, 4H), 1.80 (br d, J =14.3 Hz, 1H), 1.68 (br s, 2H), 1.12 (s, 3H) ¹⁹F NMR (377 MHz, DMSO-d₆) δ= −60.1 to −60.3 (m, 3F) [α]_(D) ²⁰ +19.1 (c 0.11, MeOH) 97% ee;absolute stereochemistry (+)-8-[(1R*,2R*)-2-hydroxy-2- unknown.methylcyclopentyl]-2-({1-[(2,2,2- Enantiomer of Ex. 86trifluoroethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 88 (A)

476 ¹H NMR (400 MHz, CD₃OD) δ = 8.57 (br s, 1H), 7.72 (d, J = 9.3 Hz,1H), 6.29 (d, J = 9.3 Hz, 1H), 6.08 (br s, 1H), 4.21 (br s, 1H),4.05-3.89 (m, 2H), 3.49-3.35 (m, 2H), 2.64-2.51 (m, 1H), 2.44-2.26 (m,2H), 2.16 (d, J = 10.3 Hz, 1H), 2.13-1.93 (m, 2H), 2.11-1.92 (m, 1H),1.84-1.55 (m, 3H), 1.12 (s, 3H) ¹⁹F NMR (377 MHz, DMSO-d₆) δ = −75.6 (brs, 3F) [α]_(D) ²⁰ −20.5 (c 0.18, MeOH) >99% ee; absolute stereochemistryunknown. (−)-8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 89methylcyclopentyl]-2-({1- [(trifluoromethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 89 (A)

476 ¹H NMR (400 MHz, CD₃OD) δ = 8.57 (br s, 1H), 7.72 (d, J = 9.3 Hz,1H), 6.29 (d, J = 9.3 Hz, 1H), 6.07 (br s, 1H), 4.21 (br s, 1H),4.04-3.88 (m, 2H), 3.39 (br s, 2H), 2.63-2.51 (m, 1H), 2.41-2.23 (m,2H), 2.22-2.05 (m, 2H), 2.01 (br d, J = 15.6 Hz, 2H), 1.79 (br d, J =13.1 Hz, 1H), 1.73-1.50 (m, 2H), 1.12 (s, 3H) ¹⁹F NMR (377 MHz, DMSO-d₆)δ = −75.6 (br s, 3F) [α]_(D) ²⁰ +19.2 (c 0.12, MeOH) 99% ee; absolutestereochemistry unknown. (+)-8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex.88 methylcyclopentyl]-2-({1- [(trifluoromethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 90 (A)

484 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.46 (d, J = 9.3Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 5.77-5.65 (m, 1H), 5.49- 5.25 (m,1H), 3.98 (br s, 1H), 3.92-3.82 (m, 2H), 3.09-2.98 (m, 2H), 2.95-2.78(m, 3H), 2.65-2.36 (m, 1H), 2.28-2.13 (m, 3H), 2.07-1.79 (m, 4H),1.76-1.61 (m, 2H), 1.20-1.09 (m, 4H), 0.78-0.69 (m, 2H), 0.43-0.34 (m,2H); [α]_(D) ²⁰ −13.1 (c 0.15, MeOH) >99% ee; absolute stereochemistryunknown. (−)-2-({1- Enantiomer of Ex. 91[(cyclopropylmethyl)sulfonyl]piperidin-4-yl}amino)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one 91 (A)

484 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.46 (d, J = 9.3Hz, 1H), 6.36 (d, J = 9.5 Hz, 1H), 5.72 (t, J = 8.3 Hz, 1H), 5.52-5.29(m, 1H), 3.99 (br s, 1H), 3.92- 3.81 (m, 2H), 3.09-2.97 (m, 2H), 2.93-2.77 (m, 3H), 2.62-2.33 (m, 1H), 2.30- 2.12 (m, 3H), 2.07-1.80 (m, 4H),1.67 (d, J = 4.8 Hz, 2H), 1.19-1.09 (m, 4H), 0.77-0.70 (m, 2H),0.41-0.36 (m, 2H); [α]_(D) ²⁰ +8.4 (c 0.21, MeOH) 93% ee; absolutestereochemistry unknown. (+)-2-({1- Enantiomer of Ex. 90[(cyclopropylmethyl)sulfonyl]piperidin-4-yl}amino)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]pyrido[2,3-d]pyrimidin-7(8H)-one 92 (A)

436 ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (br s, 1H), 7.33 (s, 1H), 5.75 (t,J = 8.3 Hz, 1H), 5.35 (br s, 1H), 3.99 (br s, 1H), 3.81 (t, J = 10.6 Hz,2H), 3.01-2.88 (m, 2H), 2.83 (s, 4H), 2.33-2.18 (m, 3H), 2.16 (s, 3H),2.10-1.79 (m, 4H), 1.75- 1.53 (m, 3H), 1.16 (s, 3H); [α]_(D) ²² −29.8 (c0.1, MeOH) >99% ee; absolute stereochemistry unknown. Enantiomer of Ex.93 (−)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-6-methyl-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one93 (A)

436 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (br s, 1H), 7.33 (s, 1H), 5.75 (t,J = 8.4 Hz, 1H), 5.41 (br s, 1H), 4.00 (br s, 1H), 3.81 (t, J = 10.6 Hz,2H), 3.02-2.88 (m, 2H), 2.83 (s, 4H), 2.33-2.18 (m, 3H), 2.16 (s, 3H),2.09-1.80 (m, 4H), 1.77- 1.58 (m, 3H), 1.16 (s, 3H); [α]_(D) ²² +31.5 (c0.1, MeOH) 99% ee; absolute stereochemistry unknown. Enantiomer of Ex.92 (+)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-6-methyl-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one94 (A)

451 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.49 (s, 1H), 7.52 (s, 1H),7.32 (br s, 1H), 6.76 (br s, 1H), 5.87 (t, J = 8.2 Hz, 1H), 4.07 (br s,1H), 3.93 (d, J = 5.9 Hz, 1H), 3.56 (t, J = 11.5 Hz, 2H), 2.86 (t, J =11.7 Hz, 2H), 2.55 (d, J = 4.6 Hz, 4H), 2.30-2.18 (m, 1H), 2.03 (s, 3H),2.00- 1.83 (m, 4H), 1.75-1.52 (m, 3H), 0.99 (s, 3H); [α]_(D) ²² −40.5 (c0.1, MeOH) >99% ee; absolute stereochemistry unknown.(−)-4-({8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 95methylcyclopentyl]-6-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-methylpiperidine-1- sulfonamide 95 (A)

451 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.49 (br s, 1H), 7.52 (br s,1H), 7.32 (br s, 1H), 6.77 (br s, 1H), 5.94-5.79 (m, 1H), 4.06 (br s,1H), 3.92 (br s, 1H), 3.56 (br s, 2H), 2.86 (t, J = 11.7 Hz, 2H), 2.55(br s, 4H), 2.24 (d, J = 10.0 Hz, 1H), 2.03 (br s, 3H), 2.00-1.81 (m,4H), 1.77- 1.48 (m, 3H), 0.99 (br s, 3H); [α]_(D) ²² +24.9 (c 0.1, MeOH)90% ee; absolute stereochemistry unknown. Enantiomer of Ex. 94(+)-4-({8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-6-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)-N-methylpiperidine-1-sulfonamide 96 (A)

543 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.37 (s, 1H), 7.32 (d, J = 1.0Hz, 1H), 5.78-5.64 (m, 1H), 5.58-5.33 (br s, 1H), 4.45-4.25 (m, 1H),4.05-3.92 (m, 3H), 3.73 (d, J = 11.3 Hz, 2H), 3.51-3.39 (m, 3H),3.12-2.92 (m, 2H), 2.85 (br s, 1H), 2.28- 2.11 (m, 6H), 2.06-1.95 (m,4H), 1.93- 1.81 (m, 2H), 1.61-1.48 (m, 3H), 1.40- 1.24 (m, 2H), 1.15 (s,3H); [α]_(D) ²² −5.0 (c 0.1, CHCl₃) 99% ee; absolute stereochemistryunknown. (−)-4-({8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 97methylcyclopentyl]-6-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-(tetrahydro-2H-pyran-4- yl)piperidine-1-sulfonamide 97 (A)

543 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.37 (s, 1H), 7.32 (s, 1H),5.71 (br s, 1H), 5.51 (br s, 1H), 4.48 (d, J = 8.0 Hz, 1H), 3.97 (d, J =11.5 Hz, 3H), 3.73 (d, J = 11.5 Hz, 2H), 3.53-3.34 (m, 3H), 3.09-2.91(m, 2H), 2.85 (br s, 1H), 2.30-2.11 (m, 6H), 2.06-1.95 (m, 4H),1.93-1.80 (m, 2H), 1.67-1.49 (m, 4H), 1.46-1.23 (m, 1H), 1.14 (s, 3H) ;[α]_(D) ²² +5.7 (c 0.1, CHCl₃) 96% ee; absolute stereochemistry unknown.(+)-4-({8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 96methylcyclopentyl]-6-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-(tetrahydro-2H-pyran-4- yl)piperidine-1-sulfonamide 98 (A)

545 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.33 (d, J = 1.3Hz, 1H), 5.78-5.69 (m, 1H), 5.51-5.18 (m, 1H), 4.62 (t, J = 5.8 Hz, 1H),4.06-3.92 (m, 1H), 3.74 (d, J = 11.0 Hz, 2H), 3.20 (s, 3H), 3.05- 2.96(m, 4H), 2.93-2.78 (m, 1H), 2.68- 2.38 (m, 1H), 2.30-2.21 (m, 1H), 2.19-2.13 (m, 5H), 2.04-1.82 (m, 4H), 1.71- 1.63 (m, 2H), 1.22 (s, 6H), 1.15(s, 3H); [α]_(D) ²² −10.9 (c 0.33, MeOH)(−)-4-({8-[(1R*,2R*)-2-hydroxy-2- >99% ee; absolute stereochemistrymethylcyclopentyl]-6-methyl-7-oxo-7,8- unknown.dihydropyrido[2,3-d]pyrimidin-2- Enantiomer of Ex. 99yl}amino)-N-(2-methoxy-2- methylpropyl)piperidine-1-sulfonamide 99 (A)

545 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.33 (d, J = 1.3Hz, 1H), 5.73 (s, 1H), 5.51-5.18 (m, 1H), 4.63 (t, J = 5.4 Hz, 1H), 3.98(br s, 1H), 3.74 (d, J = 11.3 Hz, 2H), 3.20 (s, 3H), 3.06-2.95 (m, 4H),2.86 (br s, 1H), 2.70-2.37 (m, 1H), 2.29- 2.21 (m, 1H), 2.15 (s, 5H),2.04-1.83 (m, 4H), 1.64 (br s, 2H), 1.22 (s, 6H), 1.15 (s, 3H); [α]_(D)²² +7.6 (c 0.25, MeOH) (+)-4-({8-[(1R*,2R*)-2-hydroxy-2- 99% ee;absolute stereochemistry methylcyclopentyl]-6-methyl-7-oxo-7,8- unknown.dihydropyrido[2,3-d]pyrimidin-2- Enantiomer of Ex. 98yl}amino)-N-(2-methoxy-2- methylpropyl)piperidine-1-sulfonamide 100 (A)

543 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.33 (d, J = 1.0Hz, 1H), 5.73 (t, J = 7.9 Hz, 1H), 5.37 (br s, 1H), 4.72- 4.62 (m, 1H),4.11-3.94 (m, 2H), 3.91- 3.82 (m, 1H), 3.81-3.66 (m, 3H), 3.25 (ddd, J =3.4, 7.3, 12.9 Hz, 1H), 3.09- 2.96 (m, 3H), 2.85 (br s, 1H), 2.31-2.21(m, 1H), 2.20-2.11 (m, 5H), 2.06-1.83 (m, 7H), 1.71-1.62 (m, 4H), 1.15(s, 3H); [α]_(D) ²⁰ −7.0 (c 0.1, MeOH) (−)-4-({8-[(1R*,2R*)-2-hydroxy-2-94% de; Single diastereomer. Absolutemethylcyclopentyl]-6-methyl-7-oxo-7,8- stereochemistry known (S) at THFdihydropyrido[2,3-d]pyrimidin-2- center; relative (but not absolute)yl}amino)-N-[(2S)-tetrahydrofuran-2- stereochemistry known at theylmethyl]piperidine-1-sulfonamide cyclopentyl chiral centers. Made from(S)-tetrahydro-furfurylamine and racemic Intermediate 1. 101 (A)

543 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.33 (d, J = 1.3Hz, 1H), 5.73 (t, J = 8.2 Hz, 1H), 5.36 (br s, 1H), 4.68- 4.58 (m, 1H),4.09-3.93 (m, 2H), 3.91- 3.84 (m, 1H), 3.82-3.66 (m, 3H), 3.25 (ddd, J =3.4, 7.2, 12.7 Hz, 1H), 3.10- 2.95 (m, 3H), 2.85 (br s, 1H), 2.31-2.21(m, 1H), 2.21-2.11 (m, 5H), 2.07-1.81 (m, 7H), 1.70-1.61 (m, 4H), 1.16(s, 3H); [α]_(D) ²⁰ +11 (c 0.1, MeOH)(+)-4-({8-[(1R*,2R*)-2-hydroxy-2- >99% de; Single diastereomer.methylcyclopentyl]-6-methyl-7-oxo-7,8- Absolute stereochemistry known(S) at dihydropyrido[2,3-d]pyrimidin-2- THF center; relative (but notabsolute) yl}amino)-N-[(2S)-tetrahydrofuran-2- stereochemistry known atthe ylmethyl]piperidine-1-sulfonamide cyclopentyl chiral centers. Madefrom (S)-tetrahydro-furfurylamine and racemic Intermediate 1. 102 (A)

543 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.32 (d, J = 1.3Hz, 1H), 5.72 (t, J = 8.7 Hz, 1H), 5.56 (br s, 1H), 4.95- 4.77 (m, 1H),4.08-3.92 (m, 2H), 3.86 (td, J = 6.6, 8.5 Hz, 1H), 3.80-3.64 (m, 3H),3.24 (ddd, J = 3.4, 7.0, 12.9 Hz, 1H), 3.08-2.94 (m, 3H), 2.90-2.77 (m,1H), 2.30-2.19 (m, 1H), 2.14 (d, J = 1.0 Hz, 5H), 2.04-1.80 (m, 7H),1.75-1.63 (m, 4H), 1.14 (s, 3H); (−)-4-({8-[(1R*,2R*)-2-hydroxy-2-[α]_(D) ²⁰ −23 (c 0.2, MeOH) methylcyclopentyl]-6-methyl-7-oxo-7,8- >99%de; Single diastereomer. dihydropyrido[2,3-d]pyrimidin-2- Absolutestereochemistry known (S) at yl}amino)-N-[(2R)-tetrahydrofuran-2- THFcenter; relative (but not absolute) ylmethyl]piperidine-1-sulfonamidestereochemistry known at the cyclopentyl chiral centers. Made from(R)-tetrahydro-furfurylamine and racemic Intermediate 1. 103 (A)

543 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.32 (d, J = 1.0Hz, 1H), 5.72 (t, J = 8.0 Hz, 1H), 5.55 (br s, 1H), 4.89- 4.78 (m, 1H),4.09-3.92 (m, 2H), 3.86 (td, J = 6.6, 8.3 Hz, 1H), 3.80-3.65 (m, 3H),3.24 (ddd, J = 3.5, 7.2, 12.9 Hz, 1H), 3.08-2.95 (m, 3H), 2.84 (br s,1H), 2.30- 2.19 (m, 1H), 2.14 (d, J = 1.0 Hz, 5H), 2.06-1.83 (m, 7H),1.76-1.63 (m, 4H), 1.14 (s, 3H); (+)-4-({8-[(1R*,2R*)-2-hydroxy-2-[α]_(D) ²⁰ +15.3 (c 0.2, MeOH)methylcyclopentyl]-6-methyl-7-oxo-7,8- >99% de; Single diastereomer.dihydropyrido[2,3-d]pyrimidin-2- Absolute stereochemistry known (S) atyl}amino)-N-[(2R)-tetrahydrofuran-2- THF center; relative (but notabsolute) ylmethyl]piperidine-1-sulfonamide stereochemistry known at thecyclopentyl chiral centers. Made from (R)-tetrahydro-furfurylamine andracemic Intermediate 1. 104 (A)

537 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.37 (s, 1H), 7.33 (d, J = 1.0Hz, 1H), 5.72 (br s, 1H), 5.42 (br s, 1H), 4.82 (br s, 1H), 3.99 (br s,1H), 3.74 (d, J = 11.8 Hz, 2H), 3.42 (dt, J = 6.9, 13.4 Hz, 2H),3.11-2.98 (m, 2H), 2.85 (br s, 1H), 2.27-2.21 (m, 1H), 2.20-2.11 (m,5H), 2.05-1.82 (m, 4H), 1.69 (t, J = 18.6 Hz, 6H), 1.15 (s, 3H) ¹⁹F NMR(377 MHz, DMSO-d₆) δ = −94.5 (br s, 2F) [α]_(D) ²⁰ −11 (c 0.1,MeOH) >99% ee; absolute stereochemistry(−)-N-(2,2-difluoropropyl)-4-({8- unknown. [(1R*,2R*)-2-hydroxy-2-Enantiomer of Ex. 105 methylcyclopentyl]-6-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)piperidine-1-sulfonamide 105(A)

537 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.37 (s, 1H), 7.33 (d, J = 1.3Hz, 1H), 5.72 (br s, 1H), 5.50 (br s, 1H), 4.92 (br s, 1H), 4.00 (br s,1H), 3.75 (d, J = 11.5 Hz, 2H), 3.42 (dt, J = 6.8, 13.3 Hz, 2H),3.10-2.97 (m, 2H), 2.85 (br s, 1H), 2.27-2.13 (m, 6H), 2.05-1.83 (m,4H), 1.76-1.63 (m, 6H), 1.15 (s, 3H) ¹⁹F NMR (377 MHz, DMSO-d₆) δ =−94.49 (br s, 2F) [α]_(D) ²⁰ +8.3 (c 0.1, MeOH) 99% ee; absolutestereochemistry unknown. (+)-N-(2,2-difluoropropyl)-4-({8- Enantiomer ofEx. 104 [(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-6-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)piperidine-1-sulfonamide 106(A)

562 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.33 (d, J = 1.3Hz, 1H), 5.74 (t, J = 8.4 Hz, 1H), 5.30 (br s, 1H), 4.03 (br s, 1H),3.93-3.80 (m, 3H), 3.43-3.29 (m, 3H), 3.20-3.05 (m, 3H), 2.80 (br s,1H), 2.65-2.52 (m, 2H), 2.32-2.18 (m, 3H), 2.15 (d, J = 1.0 Hz, 3H),2.06-1.80 (m, 4H), 1.70-1.60 (m, 3H), 1.15 (s, 3H); [α]_(D) ²² −55.8 (c0.2, MeOH) >99% de; Single diasteromer, absolute stereochemistryunknown; relative stereochemistry known at cyclopentyl chiral centers.(−)-2-[(1-{[(3ξ)-1,1- Peak 1 of 4, RT = 4.939 mindioxidotetrahydrothiophen-3- Chiralcel OD-3 100 × 4.6 mm 3 μmyl]sulfonyl}piperidin-4-yl)amino]-8- column; 40° C.; mobile phase 5-40%[(1R*,2R*)-2-hydroxy-2- EtOH(0.05% v/v DEA) in CO₂;methylcyclopentyl]-6-methylpyrido[2,3- 2.8 mL/mind]pyrimidin-7(8H)-one - Isomer A 107 (A)

540 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.33 (d, J = 1.0 Hz, 1H),5.73 (t, J = 8.4 Hz, 1H), 5.39 (br s, 1H), 4.03 (br s, 1H), 3.94-3.78(m, 3H), 3.45-3.29 (m, 3H), 3.19-3.08 (m, 3H), 2.81 (br s, 1H),2.65-2.51 (m, 2H), 2.32-2.17 (m, 3H), 2.14 (d, J = 0.8 Hz, 3H),2.07-1.80 (m, 4H), 1.70-1.64 (m, 3H), 1.21-1.09 (m, 3H); [α]_(D) ²² +5.9(c 0.2, MeOH) >99% de; Single diasteromer, absolute stereochemistryunknown; relative stereochemistry known at cyclopentyl chiral centers.(+)-2-[(1-{[(3ξ)-1,1- Peak 2 of 4, RT = 5.299 mindioxidotetrahydrothiophen-3- Chiralcel OD-3 100 × 4.6 mm 3 μmyl]sulfonyl}piperidin-4-yl)amino]-8- column; 40° C.; mobile phase 5-40%[(1R*,2R*)-2-hydroxy-2- EtOH(0.05% v/v DEA) in CO₂;methylcyclopentyl]-6-methylpyrido[2,3- 2.8 mL/mind]pyrimidin-7(8H)-one - Isomer B 108 (A)

540 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.33 (d, J = 1.0 Hz, 1H),5.74 (t, J = 8.5 Hz, 1H), 5.30 (br s, 1H), 4.03 (br s, 1H), 3.94-3.77(m, 3H), 3.44-3.28 (m, 3H), 3.21-3.05 (m, 3H), 2.87-2.74 (m, 1H),2.67-2.49 (m, 2H), 2.33-2.18 (m, 3H), 2.15 (d, J = 0.8 Hz, 3H),2.07-1.80 (m, 4H), 1.71-1.60 (m, 3H), 1.21-1.10 (m, 3H); [α]_(D) ²²+46.8 (c 0.2, MeOH) >99% de; Single diasteromer, absolutestereochemistry unknown; relative stereochemistry known at cyclopentylchiral centers. (+)-2-[(1-{[(3ξ)-1,1- Peak 3 of 4, RT = 5.389dioxidotetrahydrothiophen-3- Chiralcel OD-3 100 × 4.6 mm 3 μmyl]sulfonyl}piperidin-4-yl)amino]-8- column; 40° C.; mobile phase 5-40%[(1R*,2R*)-2-hydroxy-2- EtOH(0.05% v/v DEA) in CO₂;methylcyclopentyl]-6-methylpyrido[2,3- 2.8 mL/mind]pyrimidin-7(8H)-one - Isomer C 109 (A)

562 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.33 (s, 1H),5.74 (t, J = 8.0 Hz, 1H), 5.35 (br s, 1H), 4.04 (br s, 1H), 3.92- 3.80(m, 3H), 3.44-3.29 (m, 3H), 3.20- 3.07 (m, 3H), 2.81 (br s, 1H),2.64-2.51 (m, 2H), 2.33-2.18 (m, 3H), 2.15 (s, 3H), 2.07-1.80 (m, 4H),1.62 (br s, 3H), 1.15 (s, 3H); [α]_(D) ²² −3.8 (c 0.2, MeOH) 96% de;Single diasteromer, absolute stereochemistry unknown; relativestereochemistry known at cyclopentyl chiral centers. Peak 1 of 4, RT =4.939 min (−)-2-[(1-{[(3ξ)-1,1- Chiralcel OD-3 100 × 4.6 mm 3 μmdioxidotetrahydrothiophen-3- column; 40° C.; mobile phase 5-40%yl]sulfonyl}piperidin-4-yl)amino]-8- EtOH(0.05% v/v DEA) in CO₂;[(1R*,2R*)-2-hydroxy-2- 2.8 mL/minmethylcyclopentyl]-6-methylpyrido[2,3- d]pyrimidin-7(8H)-one - Isomer D110 (A)

472 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.34 (d, J = 1.0Hz, 1H), 5.76-5.71 (m, 1H), 5.42-5.19 (m, 1H), 4.00 (br s, 1H),3.88-3.79 (m, 2H), 3.07-2.96 (m, 4H), 2.84 (br s, 1H), 2.63-2.35 (m,1H), 2.31-2.16 (m, 3H), 2.15 (d, J = 1.0 Hz, 3H), 2.05-1.83 (m, 4H),1.73-1.61 (m, 2H), 1.39 (t, J = 7.4 Hz, 3H), 1.16 (s, 3H); [α]_(D) ²²−9.2 (c 0.14, MeOH) >99% ee; absolute stereochemistry unknown.Enantiomer of Ex. 111 (−)-2-{[1-(ethylsulfonyl)piperidin-4-yl]amino}-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-6-methylpyrido[2,3- d]pyrimidin-7(8H)-one 111 (A)

472 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.34 (d, J = 1.0Hz, 1H), 5.73 (t, J = 8.4 Hz, 1H), 5.40-5.19 (m, 1H), 4.07- 3.92 (m,1H), 3.88-3.79 (m, 2H), 3.07- 2.96 (m, 4H), 2.92-2.76 (m, 1H), 2.69-2.34 (m, 1H), 2.32-2.16 (m, 3H), 2.15 (d, J = 0.8 Hz, 3H), 2.06-1.83 (m,4H), 1.74-1.61 (m, 2H), 1.39 (t, J = 7.5 Hz, 3H), 1.16 (s, 3H); [α]_(D)²² +11.7 (c 0.18, MeOH) 94% ee; absolute stereochemistry unknown.(+)-2-{[1-(ethylsulfonyl)piperidin-4- Enantiomer of Ex. 110yl]amino}-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-6-methylpyrido[2,3- d]pyrimidin-7(8H)-one 112 (A)

484 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.34 (d, J = 1.0Hz, 1H), 5.76-5.71 (m, 1H), 5.44-5.20 (m, 1H), 4.06-3.90 (m, 1H),3.87-3.78 (m, 2H), 3.11-3.01 (m, 2H), 2.84 (br s, 1H), 2.51 (br s, 1H),2.33-2.17 (m, 4H), 2.15 (s, 3H), 2.05- 1.83 (m, 4H), 1.72-1.63 (m, 2H),1.22- 1.18 (m, 2H), 1.16 (s, 3H), 1.04-0.99 (m, 2H); [α]_(D) ²⁰ −15.3 (c0.13, MeOH) 95% ee; absolute stereochemistry unknown. Enantiomer of Ex.113 (−)-2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-6-methylpyrido[2,3- d]pyrimidin-7(8H)-one 113

484 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.34 (s, 1H),5.77-5.71 (m, 1H), 5.40-5.17 (m, 1H), 4.08-3.92 (m, 1H), 3.86-3.78 (m,2H), 3.10-3.01 (m, 2H), 2.84 (br s, 1H), 2.66-2.39 (m, 1H), 2.32- 2.18(m, 4H), 2.15 (s, 3H), 2.03 (br s, 4H), 1.71-1.62 (m, 2H), 1.22-1.18 (m,2H), 1.16 (s, 3H), 1.02 (dd, J = 2.3, 7.8 Hz, 2H); [α]_(D) ²⁰ +7.3 (c0.11, MeOH) >99% ee; absolute stereochemistry unknown. Enantiomer of Ex.112 (+)-2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-6-methylpyrido[2,3- d]pyrimidin-7(8H)-one 114 (A)

502 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.34 (d, J = 1.0Hz, 1H), 5.73 (t, J = 8.3 Hz, 1H), 5.30 (br s, 1H), 3.98 (br s, 1H),3.83-3.71 (m, 4H), 3.45-3.36 (m, 3H), 3.23 (t, J = 5.9 Hz, 2H),3.10-2.98 (m, 2H), 2.85 (br s, 1H), 2.50 (d, J = 7.5 Hz, 1H), 2.30-2.17(m, 2H), 2.15 (d, J = 1.0 Hz, 3H), 2.07-1.81 (m, 4H), 1.65 (d, J = 11.0Hz, 2H), 1.16 (s, 3H); [α]_(D) ²⁰ −7.7 (c 0.20, CHCl₃) 97% ee; absolutestereochemistry unknown. (−)-8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex.115 methylcyclopentyl]-2-({1-[(2- methoxyethyl)sulfonyl]piperidin-4-yl}amino)-6-methylpyrido[2,3- d]pyrimidin-7(8H)-one 115 (A)

502 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.34 (d, J = 1.0Hz, 1H), 5.73 (t, J = 8.4 Hz, 1H), 5.27 (s, 1H), 3.99 (br s, 1H), 3.77(t, J = 5.9 Hz, 4H), 3.41 (s, 3H), 3.23 (t, J = 5.9 Hz, 2H), 3.10-2.95(m, 2H), 2.87 (s, 1H), 2.46 (s, 1H), 2.28- 2.17 (m, 2H), 2.15 (s, 3H),2.07-1.79 (m, 4H), 1.71-1.57 (m, 2H), 1.16 (s, 3H); [α]_(D) ²⁰ +1.6 (c0.12, CHCl₃) 98% ee; absolute stereochemistry unknown. Enantiomer of Ex.114 (+)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-2-({1-[(2-methoxyethyl)sulfonyl]piperidin-4- yl}amino)-6-methylpyrido[2,3-d]pyrimidin-7(8H)-one 116 (A)

498 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.34 (d, J = 1.0Hz, 1H), 5.73 (t, J = 8.4 Hz, 1H), 5.26 (br s, 1H), 3.99 (br s, 1H),3.91-3.79 (m, 2H), 3.09-2.97 (m, 2H), 2.90 (d, J = 7.0 Hz, 3H),2.62-2.38 (m, 1H), 2.30-2.18 (m, 2H), 2.15 (d, J = 1.0 Hz, 3H),2.07-1.81 (m, 4H), 1.72- 1.58 (m, 2H), 1.19-1.08 (m, 4H), 0.77- 0.65 (m,2H), 0.43-0.31 (m, 2H); [α]_(D) ²⁰ −3.9 (c 0.19, CHCl₃) >99% ee;absolute stereochemistry unknown. (−)-2-({1- Enantiomer of Ex. 117[(cyclopropylmethyl)sulfonyl]piperidin-4-yl}amino)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-6-methylpyrido[2,3- d]pyrimidin-7(8H)-one 117 (A)

498 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.33 (d, J = 1.0Hz, 1H), 5.73 (t, J = 8.4 Hz, 1H), 5.30 (br s, 1H), 3.98 (br s, 1H),3.86 (t, J = 10.8 Hz, 2H), 3.09- 2.97 (m, 2H), 2.92-2.76 (m, 3H), 2.50(br s, 1H), 2.30-2.18 (m, 2H), 2.14 (d, J = 1.0 Hz, 3H), 2.07-1.81 (m,4H), 1.65 (dd, J = 3.9, 11.2 Hz, 2H), 1.18-1.08 (m, 4H), 0.77-0.69 (m,2H), 0.38 (q, J = 5.0 Hz, 2H); [α]_(D) ²⁰ +2.8 (c 0.14, CHCl₃) 94% ee;absolute stereochemistry (+)-2-({1- unknown.[(cyclopropylmethyl)sulfonyl]piperidin- Enantiomer of Ex. 1164-yl}amino)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-6-methylpyrido[2,3- d]pyrimidin-7(8H)-one 118 (A)

526 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.36-7.32 (m,1H), 5.78-5.71 (m, 1H), 4.11-3.98 (m, 1H), 3.94-3.86 (m, 2H), 3.74 (q, J= 9.3 Hz, 2H), 3.10 (d, J = 10.8 Hz, 2H), 2.90-2.77 (m, 1H), 2.29-2.18(m, 3H), 2.15 (s, 3H), 2.06- 1.83 (m, 4H), 1.73-1.65 (m, 2H), 1.16 (s,3H); [α]_(D) ²⁰ −17.6 (c 0.07, MeOH) >99% ee; absolute stereochemistryunknown. Enantiomer of Ex. 119 (−)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-6-methyl-2-({1-[(2,2,2-trifluoroethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin- 7(8H)-one 119 (A)

526 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.34 (d, J = 1.3Hz, 1H), 5.77-5.72 (m, 1H), 4.11-3.98 (m, 1H), 3.95-3.85 (m, 2H), 3.74(q, J = 9.4 Hz, 2H), 3.16- 3.04 (m, 2H), 2.90-2.77 (m, 1H), 2.29- 2.19(m, 3H), 2.15 (d, J = 1.0 Hz, 3H), 2.07-1.82 (m, 4H), 1.73-1.65 (m, 2H),1.16 (s, 3H); [α]_(D) ²⁰ +14.0 (c 0.09, MeOH) 99% ee; absolutestereochemistry unknown. Enantiomer of Ex. 118(+)-8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-6-methyl-2-({1-[(2,2,2-trifluoroethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin- 7(8H)-one 120 (F)

483 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.51 (s, 1H), 7.72 (s, 1H),5.78 (br s, 1H), 5.50 (br s, 1H), 3.97 (s, 1H), 3.84 (d, J = 12.3 Hz,2H), 3.69-3.60 (m, 2H), 3.01-2.87 (m, 2H), 2.83 (s, 3H), 2.76 (br s,1H), 2.41-2.14 (m, 4H), 2.09-1.80 (m, 4H), 1.74-1.61 (m, 2H), 1.15 (s,3H); [α]_(D) ²⁰ −10 (c 0.12, MeOH) >99% ee; absolute stereochemistryunknown. Enantiomer of Ex. 121 (−)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)acetonitrile 121 (F)

483 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.51 (s, 1H), 7.72 (s, 1H),5.78 (br s, 1H), 5.58- 5.37 (m, 1H), 3.96 (br s, 1H), 3.84 (d, J = 11.8Hz, 2H), 3.66 (br s, 2H), 2.98- 2.86 (m, 2H), 2.83 (s, 3H), 2.75 (br s,1H), 2.40-2.12 (m, 4H), 2.07-1.79 (m, 4H), 1.75-1.63 (m, 2H), 1.14 (s,3H); [α]_(D) ²⁰ +8.5 (c 0.13, MeOH) >99% ee; absolute stereochemistryunknown. Enantiomer of Ex. 120 (+)-(8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)acetonitrile 122 (A)

488 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.41 (s, 1H),5.75 (t, J = 8.0 Hz, 1H), 5.51-5.26 (m, 1H), 4.10-3.92 (m, 1H), 3.83 (d,J = 14.8 Hz, 4H), 2.99-2.86 (m, 2H), 2.82 (s, 7H), 2.31-2.16 (m, 3H),2.08-1.78 (m, 4H), 1.76-1.63 (m, 3H), 1.15 (s, 3H); [α]_(D) ²⁰ −6.3 (c0.14, CHCl₃) >99% ee; absolute stereochemistry unknown. Enantiomer ofEx. 123 (−)-6-(2-hydroxyethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 123 (A)

488 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.42 (s, 1H),5.79 (t, J = 12.0 Hz, 1H), 5.52-5.24 (m, 1H), 4.10-3.93 (m, 1H),3.91-3.73 (m, 4H), 3.00-2.87 (m, 2H), 2.85-2.66 (m, 7H), 2.33-2.17 (m,3H), 2.09-1.78 (m, 4H), 1.75-1.63 (m, 3H), 1.16 (s, 3H); [α]_(D) ²⁰ +7.1(c 0.13, CHCl₃) >99% ee; absolute stereochemistry unknown. Enantiomer ofEx. 122 (+)-6-(2-hydroxyethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 124 (B)

455 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.58 (br s, 1H), 7.84 (br s, 1H),7.73-7.64 (m, 1H), 7.03 (d, J = 4.6 Hz, 1H), 5.89 (br s, 1H), 4.52-4.30(m, 1H), 4.03-3.82 (m, 1H), 3.57-3.44 (m, 2H), 2.89-2.75 (m, 2H), 2.52(d, J = 4.6 Hz, 3H), 2.47-2.31 (m, 1H), 2.25-2.08 (m, 2H), 1.96 (br s,2H), 1.87 (br s, 2H), 1.69 (d, J = 11.0 Hz, 1H), 1.60 (d, J = 11.0 Hz,1H), 1.45 (d, J = 9.9 Hz, 1H), 0.97 (br s, 3H) ¹⁹F NMR (377 MHz,DMSO-d₆) δ = −136.1 (d, J = 148.8 Hz, 1F)(−)-4-({6-fluoro-8-[(1R*,2R*)-2- [α]_(D) ²⁰ −17.6 (c 0.1, CHCl₃)hydroxy-2-methylcyclopentyl]-7-oxo- 98% ee; absolute stereochemistry7,8-dihydropyrido[2,3-d]pyrimidin-2- unknown.yl}amino)-N-methylpiperidine-1- Enantiomer of Ex. 125 sulfonamide 125(B)

437 [M − H₂O + H]⁺ ¹H NMR (700 MHz, DMSO-d₆) δ = 8.58 (br s, 1H), 7.84(br s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.03 (br s, 1H), 5.89 (br s, 1H),4.49-4.31 (m, 1H), 4.05-3.79 (m, 1H), 3.61-3.42 (m, 2H), 2.81 (br s,2H), 2.52 (br s, 3H), 2.27-2.04 (m, 2H), 1.96 (br s, 2H), 1.90-1.82 (m,2H), 1.69 (d, J = 9.0 Hz, 1H), 1.60 (d, J = 10.3 Hz, 1H), 1.45 (br s,1H), 0.98 (br s, 3H) ¹⁹F NMR (377 MHz, DMSO-d₆) δ = −135.6 to −136.6 (m,1F) [α]_(D) ²⁰ +18.2 (c 0.1, CHCl₃)(+)-4-({6-fluoro-8-[(1R*,2R*)-2- >95% ee; absolute stereochemistryhydroxy-2-methylcyclopentyl]-7-oxo- unknown.7,8-dihydropyrido[2,3-d]pyrimidin-2- Enantiomer of Ex. 124yl}amino)-N-methylpiperidine-1- sulfonamide 126 (D)

471 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.59 (s, 1H), 8.01 (s, 1H),7.60 (br s, 1H), 6.70 (br s, 1H), 5.91 (t, J = 8.2 Hz, 1H), 4.09 (br s,1H), 4.02-3.90 (m, 1H), 3.57 (t, J = 11.3 Hz, 2H), 2.88 (t, J = 11.9 Hz,2H), 2.56 (d, J = 5.0 Hz, 3H), 2.26- 2.13 (m, 1H), 2.12-1.95 (m, 3H),1.93- 1.82 (m, 2H), 1.76-1.51 (m, 3H), 1.01 (s, 3H) [α]_(D) ²² −13.5 (c0.1, CHCl₃) >99% ee; absolute stereochemistry unknown.(−)-4-({6-chloro-8-[(1R*,2R*)-2- Enantiomer of Ex. 127hydroxy-2-methylcyclopentyl]-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-methylpiperidine-1- sulfonamide 127 (D)

471 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.59 (s, 1H), 8.01 (s, 1H),7.60 (br s, 1H), 6.70 (br s, 1H), 5.91 (t, J = 8.1 Hz, 1H), 4.09 (br s,1H), 3.96 (br s, 1H), 3.57 (t, J = 11.2 Hz, 2H), 2.88 (t, J = 11.8 Hz,2H), 2.56 (d, J = 4.9 Hz, 3H), 2.26- 2.13 (m, 1H), 2.11-1.84 (m, 5H),1.78- 1.52 (m, 3H), 1.01(s, 3H) [α]_(D) ²² +14.4 (c 0.1, CHCl₃) >99% ee;absolute stereochemistry unknown. Enantiomer of Ex. 126(+)-4-({6-chloro-8-[(1R*,2R*)-2- hydroxy-2-methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)-N-methylpiperidine-1-sulfonamide 128 (D)

457 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.50 (s, 1H), 7.93 (s, 1H),7.47 (br s, 1H), 6.38 (br s, 2H), 5.82 (t, J = 8.3 Hz, 1H), 3.99 (br s,1H), 3.82 (br s, 1H), 3.45 (t, J = 10.8 Hz, 2H), 2.66 (t, J = 11.7 Hz,2H), 2.05-2.16 (m, 1H), 1.98 (d, J = 10.6 Hz, 1H), 1.91 (d, J = 10.5 Hz,2H), 1.81 (br s, 2H), 1.60-1.69 (m, 2H), 1.47-1.60 (m, 2H), 0.92 (s, 3H)[α]_(D) ²² −20.2 (c 0.1, CHCl₃w/~10% MeOH) 97% ee; absolutestereochemistry (−)-4-({6-chloro-8-[(1R*,2R*)-2- unknown.hydroxy-2-methylcyclopentyl]-7-oxo- Enantiomer of Ex. 1297,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)piperidine-1-sulfonamide129 (D)

457 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.50 (s, 1H), 7.92 (s, 1H),7.46 (br s, 1H), 6.38 (br s, 2H), 5.82 (t, J = 8.2 Hz, 1H), 3.98 (br s,1H), 3.82 (br s, 1H), 3.45 (t, J = 10.7 Hz, 2H), 2.66 (t, J = 11.8 Hz,2H), 2.05-2.19 (m, 1H), 1.85-2.04 (m, 3H), 1.72-1.85 (m, 2H), 1.60-1.69(m, 2H), 1.40-1.60 (m, 2H), 0.93 (s, 3H) [α]_(D) ²² +18.6 (c 0.1, CHCl₃w/~10% MeOH) 99% ee; absolute stereochemistry unknown.(+)-4-({6-chloro-8-[(1R*,2R*)-2- Enantiomer of Ex. 128hydroxy-2-methylcyclopentyl]-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2-yl}amino)piperidine-1-sulfonamide 130 (E)

487 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.72 (s, 1H), 8.03 (s, 1H),7.76 (br s, 1H), 6.83 (t, J = 55.0 Hz, 2H), 6.71 (br s, 1H), 5.87 (t, J= 8.3 Hz, 1H), 4.09 (br s, 1H), 3.99 (d, J = 9.2 Hz, 1H), 3.58 (t, J =12.2 Hz, 2H), 2.88 (t, J = 11.8 Hz, 2H), 2.56 (br s, 3H), 2.26-2.13 (m,1H), 2.12- 1.80 (m, 5H), 1.77-1.51 (m, 3H), 1.03 (s, 3H) ¹⁹F NMR (377MHz, DMSO-d₆, 30° C.) δ = −117.1 to −117.2 (m, 2F) [α]_(D) ²² −21.5 (c0.2, CHCl₃ w/~10% (−)-4-({6-(difluoromethyl)-8-[(1R*,2R*)- MeOH)2-hydroxy-2-methylcyclopentyl]-7-oxo- 90% ee; absolute stereochemistry7,8-dihydropyrido[2,3-d]pyrimidin-2- unknown.yl}amino)-N-methylpiperidine-1- Enantiomer of Ex. 131 sulfonamide 131(E)

487 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.72 (s, 1H), 8.03 (s, 1H),7.76 (br s, 1H), 6.83 (t, J = 54.0 Hz, 1H), 6.71 (s, 1H), 5.86 (t, J =8.1 Hz, 1H), 4.08 (br s, 1H), 3.97 (br s, 1H), 3.75 (br s, 1H), 3.58 (brs, 2H), 2.88 (t, J = 11.8 Hz, 2H), 2.56 (br s, 3H), 2.26-2.13 (m, 1H),2.11- 1.94 (m, 3H), 1.89 (br s, 2H), 1.77-1.52 (m, 3H), 1.03 (s, 3H) ¹⁹FNMR (377 MHz, DMSO-d₆, 30° C.) δ = −117.1 to −117.2 (m, 2F) [α]_(D) ²²+20.1 (c 0.1, CHCl₃ w/~10% (+)-4-({6-(difluoromethyl)-8-[(1R*,2R*)-MeOH) 2-hydroxy-2-methylcyclopentyl]-7-oxo- 98% ee; absolutestereochemistry 7,8-dihydropyrido[2,3-d]pyrimidin-2- unknown.yl}amino)-N-methylpiperidine-1- Enantiomer of Ex. 130 sulfonamide 132(E)

490 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.66 (s, 1H), 8.16 (s, 1H),7.84 (d, J = 7.6 Hz, 1H), 5.62-5.92 (m, 1H), 4.00 (s, 1H), 3.95 (br s,1H), 3.54 (t, J = 11.5 Hz, 2H), 2.80-2.89 (m, 2H), 2.78 (s, 3H),2.05-2.16 (m, 1H), 2.00 (br s, 1H), 1.85- 1.96 (m, 2H), 1.73-1.85 (m,2H), 1.58- 1.70 (m, 2H), 1.42-1.58 (m, 1H), 0.94 (s, 3H) ¹⁹F NMR (377MHz, DMSO-d₆) δ = −63.28 to −63.42 (m, 3F) [α]_(D) ²² −19.6 (c 0.1,CHCl₃) 8-[(1R,2R)-2-hydroxy-2- >99% ee; Single enantiomer, absolutemethylcyclopentyl]-2-{[1- stereochemistry known.(methylsulfonyl)piperidin-4-yl]amino}-6-(trifluoromethyl)pyrido[2,3-d]pyrimidin- 7(8H)-one 133-140 in methodstext 141 (A)

420 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.52 (s, 1H), 7.47 (s, 1H), 7.37-7.11(m, 1H), 5.85 (s, 1H), 4.08-3.86 (m, 1H), 3.62 (d, J = 12.5 Hz, 2H),2.97-2.89 (m, 2H), 2.88 (s, 3H), 2.47 (q, J = 7.6 Hz, 2H), 2.33 (m, 2H),2.09-1.93 (m, 4H), 1.84-1.73 (m, 2H), 1.72-1.57 (m, 4H), 1.15 (t, J =7.4 Hz, 3H) 8-cyclopentyl-6-ethyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 142 (A)

458 [M + Na]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ = 8.43 (s, 1H), 7.53 (s, 1H),5.90-5.85 (m, 1H), 5.30 (m, 1H), 4.40 (s, 2H), 4.95-4.10 (m, 1H),3.85-3.70 (m, 2H), 3.50 (s, 3H), 2.94-2.75 (m, 5H), 2.40-2.25 (m, 2H),2.19-2.22 (m, 2H), 1.95-2.10 (m, 2H), 1.80-1.75 (m, 2H), 1.70-1.60 (m,4H) 8-cyclopentyl-6-(methoxymethyl)-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 143 (A)

422 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.59 (s, 1H), 7.64 (s, 1H),7.33 (br s, 1H), 5.85 (quin, J = 8.8 Hz, 1H), 4.79 (br s, 1H), 4.36 (brs, 2H), 3.98 (br s, 1H), 3.66-3.58 (m, 2H), 2.96-2.90 (m, 2H), 2.88 (s,3H), 2.40-2.25 (m, 2H), 2.07- 1.95 (m, 4H), 1.85-1.73 (m, 2H), 1.72-1.60 (m, 4H) 8-cyclopentyl-6-(hydroxymethyl)-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one144 (A)

450 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.38 (s, 1H), 5.88 (quin,J = 8.8 Hz, 1H), 5.23 (br s, 1H), 4.03 (br d, J = 7.0 Hz, 1H), 3.80 (brd, J = 12.0 Hz, 2H), 3.65 (t, J = 6.1 Hz, 2H), 3.36 (s, 3H), 3.01-2.89(m, 2H), 2.87-2.79 (m, 5H), 2.35 (br s, 2H), 2.20 (br dd, J = 3.1, 13.4Hz, 2H), 2.10-1.99 (m, 2H), 1.92-1.79 (m, 2H), 1.76-1.63 (m, 4H)8-cyclopentyl-6-(2-methoxyethyl)-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 145 (A)

436 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.52 (s, 1H), 7.52 (s, 1H), 7.29 (d, J= 7.8 Hz, 1H), 5.86 (quin, J = 8.9 Hz, 1H), 4.24 (br s, 1H), 3.72-3.50(m, 5H), 2.98-2.85 (m, 5H), 2.63 (t, J = 6.5 Hz, 2H), 2.41-2.24 (m, 2H),2.10-1.94 (m, 4H), 1.85-1.73 (m, 2H), 1.73-1.61 (m, 4H)8-cyclopentyl-6-(2-hydroxyethyl)-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 146 (A)

451 ¹H NMR (400 MHz, CDCl₃) δ = 8.40 (s, 1H), 7.38 (s, 1H), 5.89 (quin,J = 8.8 Hz, 1H), 5.31 (s, 1H), 4.19-4.10 (m, 1H), 4.03 (br s, 1H), 3.87(t, J = 5.6 Hz, 2H), 3.74 (br d, J = 12.8 Hz, 2H), 3.10-2.98 (m, 2H),2.83 (t, J = 5.5 Hz, 2H), 2.77 (d, J = 5.5 Hz, 3H), 2.35 (br s, 2H),2.16 (br dd, J = 3.4, 13.2 Hz, 2H), 2.04 (br s, 2H), 1.92-1.80 (m, 2H),1.74-1.65 (m, J = 10.5 Hz, 4H) 4-{[8-cyclopentyl-6-(2-hydroxyethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 2-yl]amino}-N-methylpiperidine-1-sulfonamide 147 (F)

450 ¹H NMR (400 MHz, DMSO-d₆ + D₂O) δ = 8.54 (br s, 1H), 7.60 (s, 1H),5.77 (br s, 1H), 4.01-3.89 (m, 1H), 3.62-3.50 (m, 2H), 3.42-3.31 (m,2H), 2.92-2.77 (m, 5H), 2.24 (br s, 1H), 2.17-2.05 (m, 1H), 2.05-1.86(m, 4H), 1.80-1.50 (m, 6H) (8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)acetic acid 148 (E)

460 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.75 (s, 1H), 8.24 (s, 1H), 7.93 (brs, 1H), 5.83 (quin, J = 8.8 Hz, 1H), 4.05 (dd, J = 6.48, 13.45 Hz, 1H),3.64 (td, J = 3.42, 12.47 Hz, 2H), 2.99-2.90 (m, 2H), 2.89 (s, 3H), 2.31(br s, 2H), 2.06-1.95 (m, 4H), 1.88-1.76 (m, 2H), 1.74-1.59 (m, 4H) ¹⁹FNMR (377 MHz, DMSO-d₆) δ = −69.27 to −61.50 (m, 3F) 8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-6-(trifluoromethyl)pyrido[2,3-d]pyrimidin- 7(8H)-one 149 (C)

456 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (br s, 1H), 7.45 (s, 1H), 6.12 (tt,J = 4.6, 57.0 Hz, 1H), 5.84 (quin, J = 8.9 Hz, 1H), 4.18-4.03 (m, 1H),3.72 (br s, 1H), 3.10 (dt, J = 4.5, 16.4 Hz, 4H), 2.86 (s, 3H), 2.31 (brs, 2H), 2.24-2.13 (m, 3H), 2.11- 1.98 (m, 3H), 1.95-1.82 (m, 5H) ¹⁹F NMR(376 MHz, CDCl₃) δ = −115.4 (td, J = 16.0, 57.2 Hz, 1F)8-cyclopentyl-6-(2,2-difluoroethyl)-2- {[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 150 (H)

425 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.40 (br s, 1H), 7.15 (br s, 1H), 6.62(s, 1H), 5.91 (br s, 1H), 5.16 (br s, 2H), 4.92 (d, J = 49.1 Hz, 1H),4.14-3.98 (m, 1H), 3.85 (t, J = 11.4 Hz, 1H), 3.13 (dd, J = 13.6, 37.6Hz, 2H), 3.02-2.94 (m, 1H), 2.91 (s, 3H), 2.19 (br s, 2H), 2.03-1.86 (m,3H), 1.82-1.73 (m, 3H), 1.61 (br s, 2H) Peak 2 of 2, RT = 2.306 minChiralcel OJ-3 4.6 × 100 mm 3 μm column; 30% MeOH/DEA @ 120 bar, 4mL/min 6-amino-8-cyclopentyl-2-{[(3R*,4S*)-3- 99% ee; absolutestereochemistry fluoro-1-(methylsulfonyl)piperidin-4- unknownyl]amino}pyrido[2,3-d]pyrimidin-7(8H)- Enantiomer of Ex. 151 one -Isomer B 151 (H)

425 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.40 (s, 1H), 7.15 (br s, 1H), 6.62(s, 1H), 5.91 (br s, 1H), 5.16 (s, 2H), 4.92 (d, J = 48.9 Hz, 1H),4.17-3.99 (m, 1H), 3.85 (t, J = 10.6 Hz, 1H), 3.13 (dd, J = 13.6, 37.4Hz, 2H), 2.97 (t, J = 11.4 Hz, 1H), 2.91 (s, 3H), 2.19 (br s, 2H),2.01-1.87 (m, 3H), 1.83-1.72 (m, 3H), 1.61 (br s, 2H) Peak 1 of 2, RT =1.212 min Chiralcel OJ-3 4.6 × 100 mm 3 μm column; 30% MeOH/DEA @ 120bar, 4 6-amino-8-cyclopentyl-2-{[(3R*,4S*)-3- mL/minfluoro-1-(methylsulfonyl)piperidin-4- 99% ee; absolute stereochemistryyl]amino}pyrido[2,3-d]pyrimidin-7(8H)- unknown one - Isomer A Enantiomerof Ex. 150 152 (D)

444 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.58 (d, J = 7.2 Hz, 1H), 8.05-7.77(m, 2H), 5.96-5.64 (m, 1H), 5.08-4.72 (m, 1H), 4.26-3.97 (m, 1H),3.91-3.73 (m, 1H), 3.61 (br s, 1H), 3.17-3.04 (m, 1H), 2.95 (br s, 1H),2.87 (d, J = 15.2 Hz, 3H), 2.10 (br s, 2H), 1.91 (d, J = 15.0 Hz, 3H),1.74 (br s, 3H), 1.65-1.47 (m, 2H) [α]_(D) ²² −70.3 (c 0.1, MeOH) >99%ee; absolute stereochemistry unknown. Enantiomer of Ex. 153(−)-6-chloro-8-cyclopentyl-2- {[(3R*,4S*)-3-fluoro-1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one153 (D)

444 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.63 (d, J = 11.3 Hz, 1H), 8.26-7.81(m, 2H), 6.09-5.72 (m, 1H), 5.08-4.73 (m, 1H), 4.38-4.00 (m, 1H),3.93-3.77 (m, 1H), 3.24-3.08 (m, 1H), 2.99 (d, J = 9.7 Hz, 1H), 2.91 (d,J = 17.6 Hz, 3H), 2.15 (br s, 2H), 2.04-1.89 (m, 4H), 1.79 (br s, 3H),1.67-1.53 (m, 2H) ¹⁹F NMR (376 MHz, DMSO-d₆) δ = −200.6 (d, J = 251.8Hz, 1F) [α]_(D) ²² +70.5 (c 0.1, MeOH) >99% ee; absolute stereochemistry(+)-6-chloro-8-cyclopentyl-2- unknown. {[(3R*,4S*)-3-fluoro-1-Enantiomer of Ex. 152 (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 154 (D)

444 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.58 (d, J = 16.2 Hz, 1H), 8.21-7.81(m, 2H), 5.96-5.69 (m, 1H), 4.88-4.48 (m, 1H), 4.37-4.00 (m, 1H),3.79-3.61 (m, 1H), 3.49 (s, 1H), 3.18-2.93 (m, 2H), 2.90 (br s, 3H),2.21 (d, J = 7.3 Hz, 1H), 2.12-1.88 (m, 4H), 1.72 (br s, 2H), 1.66-1.42(m, 3H) [α]_(D) ²² −5.3 (c 0.1, MeOH) >99% ee; absolute stereochemistryunknown. Enantiomer of Ex. 155 (−)-6-chloro-8-cyclopentyl-2-{[(3S*,4S*)-3-fluoro-1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 155 (D)

444 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.58 (d, J = 15.5 Hz, 1H), 8.27-7.69(m, 2H), 6.10-5.25 (m, 1H), 4.80-4.47 (m, 1H), 4.31-4.01 (m, 1H),3.73-3.58 (m, 1H), 3.51-3.38 (m, 1H), 3.16-2.92 (m, 2H), 2.90 (br s,3H), 2.21 (br s, 1H), 2.12- 1.84 (m, 4H), 1.73 (br s, 2H), 1.66-1.42 (m,3H) ¹⁹F NMR (376 MHz, DMSO-d₆) δ = −186.8 (d, J = 144.2 Hz, 1F) [α]_(D)²² +4.1 (c 0.1, MeOH) ~98.8% ee, absolute stereochemistry(+)-6-chloro-8-cyclopentyl-2- unknown. {[(3S*,4S*)-3-fluoro-1-Enantiomer of Ex. 154 (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 156 (G)

455 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ 8.54 (s, 1H), 7.53 (s, 2H),5.94-5.75 (m, 1H), 4.73 (d, J = 49.0 Hz, 1H), 4.25 (br s, 2H), 3.84-3.72(m, 1H), 3.63 (q, J = 5.7 Hz, 2H), 3.55 (d, J = 11.2 Hz, 1H), 3.15-3.07(m, 1H), 2.95 (s, 3H), 2.68- 2.60 (m, 2H), 2.32 (br s, 2H), 2.14-1.93(m, 3H), 1.85-1.59 (m, 5H) [α]_(D) ²² −4.9 (c 0.1, MeOH) 96% ee;absolute stereochemistry unknown. Enantiomer of Ex. 157(−)-8-cyclopentyl-2-{[(3S*,4S*)-3- fluoro-1-(methylsulfonyl)piperidin-4-yl]amino}-6-(2-hydroxyethyl)pyrido[2,3- d]pyrimidin-7(8H)-one 157 (G)

455 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.54 (s, 1H), 7.53 (br s, 2H),5.85 (t, J = 8.8 Hz, 1H), 4.73 (d, J = 49.0 Hz, 1H), 4.26 (br s, 2H),3.86-3.48 (m, 4H), 3.16- 3.06 (m, 1H), 2.95 (s, 3H), 2.63 (br s, 2H),2.32 (br s, 2H), 2.16-1.94 (m, 3H), 1.86-1.57 (m, 5H) [α]_(D) ²² +17.6(c 0.1, MeOH) 99% ee; absolute stereochemistry unknown. Enantiomer ofEx. 156 (+)-8-cyclopentyl-2-{[(3S*,4S*)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl]amino}-6-(2-hydroxyethyl)pyrido[2,3- d]pyrimidin-7(8H)-one 158 (G)

468 ¹H NMR (400 MHz, CDCl₃) δ = 8.40 (s, 1H), 7.38 (s, 1H), 5.92-5.83(m, 1H), 5.29 (br s, 1H), 4.74-4.60 (m, 1H), 4.30 (br s, 1H), 3.95-3.92(m, 1H), 3.67-3.63 (m, 3H), 3.36 (s, 3H), 3.21-3.18 (m, 2H), 2.90 (s,3H), 2.84-2.80 (m, 2H), 2.36- 2.35 (m, 3H), 2.05 (br s, 2H), 1.85-1.69(m, 5H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ = −186.8 (d, J = 130.5 Hz, 1F)[α]_(D) ²² −12.9 (c 0.10, CHCl₃) 99% ee; absolute stereochemistry(−)-8-cyclopentyl-2-{[(3S*,4S*)-3- unknown.fluoro-1-(methylsulfonyl)piperidin-4- Enantiomer of Ex. 159yl]amino}-6-(2- methoxyethyl)pyrido[2,3-d]pyrimidin- 7(8H)-one 159 (G)

468 ¹H NMR (400 MHz, CDCl₃) δ = 8.41 (s, 1H), 7.39 (s, 1H), 5.88 (quin,J = 9.0 Hz, 1H), 5.29 (br s, 1H), 4.85-4.55 (m, 1H), 4.31 (br d, J = 4.5Hz, 1H), 4.00-3.86 (m, 1H), 3.66 (t, J = 6.1 Hz, 3H), 3.40-3.34 (m, 3H),3.20 (br d, J = 12.0 Hz, 2H), 2.91 (s, 3H), 2.83 (t, J = 5.9 Hz, 2H),2.43-2.26 (m, 3H), 2.06 (br s, 2H), 1.92- 1.65 (m, 5H) ¹⁹F NMR (376 MHz,DMSO-d₆, 80° C.) δ −186.4 (s, 1F) [α]_(D) ²² +2.86 (c 0.105, CHCl₃)(+)-8-cyclopentyl-2-{[(3S*,4S*)-3- 99% ee; absolute stereochemistryfluoro-1-(methylsulfonyl)piperidin-4- unknown. yl]amino}-6-(2-Enantiomer of Ex. 158 methoxyethyl)pyrido[2,3-d]pyrimidin- 7(8H)-one 160(F)

467 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.61 (s, 1H), 8.03-7.72 (m, 1H), 7.60(s, 1H), 7.34 (br s, 1H), 6.85 (br s, 1H), 6.01- 5.71 (m, 1H), 4.83-4.57(m, 1H), 4.40- 4.10 (m, 1H), 3.74 (br s, 1H), 3.49 (br s, 1H), 3.25 (s,2H), 3.13 (br s, 1H), 3.04 (br t, J = 11.0 Hz, 1H), 2.96 (s, 3H), 2.27-1.90 (m, 5H), 1.80-1.56 (m, 5H) ¹⁹F NMR (376 MHz, DMSO-d₆, 80° C.) δ =−186.4 (s, 1F) [α]_(D) ²² −12.5 (c 0.1, DMSO) Single enantiomer,absolute (−)-2-(8-cyclopentyl-2-{[(3S*,4S*)-3- stereochemistry unknown.fluoro-1-(methylsulfonyl)piperidin-4- Enantiomer of Ex. 161yl]amino}-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)acetamide 161(F)

467 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.62 (s, 1H), 7.96-7.78 (d, 1H), 7.61(s, 1H), 7.35 (s, 1H), 6.86 (s, 1H), 5.81 (m, 1H), 4.76-4.64 (m, 1H),4.33-4.22 (m, 1H), 3.74 (br s, 1H), 3.49 (br s, 1H), 3.27- 3.26 (m, 2H),3.13-3.07 (m, 1H), 3.04- 3.02 (m, 1H), 2.97 (s, 3H), 2.17-1.98 (m, 5H),1.75-1.66 (m, 5H). Single enantiomer, absolute stereochemistry unknown.Enantiomer of Ex. 160 (+)-2-(8-cyclopentyl-2-{[(3S*,4S*)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)acetamide 162(G)

465 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.56 (d, J = 7.3 Hz, 1H) 8.53 (br s,1H) 7.66 (d, J = 6.8 Hz, 1H) 7.53 (br s, 2H) 5.86 (t, J = 8.7 Hz, 1H)4.61 (br s, 1H) 4.08 (br s, 1H) 3.11 (t, J = 12.0 Hz, 2H) 2.97 (s, 4H)2.57 (t, J = 6.3 Hz, 3H) 1.96 (d, J = 12.3 Hz, 4H) 1.74 (br s, 4H) 1.60(br s, 2H) 1.50 (s, 6H) [α]_(D) ²² +71.2 (c 0.1, MeOH) 99% ee; absolutestereochemistry unknown. Enantiomer of Ex. 163(+)-8-cyclopentyl-2-{[2,2-dimethyl-1-(methylsulfonyl)piperidin-4-yl]amino}-6-(2-hydroxyethyl)pyrido[2,3-d]pyrimidin- 7(8H)-one 163 (G)

465 ¹H NMR (700 MHz, DMSO-d₆) δ 8.56 (d, J = 7.3 Hz, 1H) 8.53 (br s, 1H)7.66 (d, J = 6.8 Hz, 1H) 7.53 (br s, 2H) 5.86 (t, J = 8.7 Hz, 1H) 4.61(br s, 1H) 4.08 (br s, 1H) 3.11 (t, J = 12.0 Hz, 2H) 2.97 (s, 4H) 2.57(t, J = 6.3 Hz, 3H) 1.96 (d, J = 12.3 Hz, 4H) 1.74 (br s, 4H) 1.60 (brs, 2H) 1.50 (s, 6H) [α]_(D) ²² −70.7 (c 0.1, MeOH) 99% ee; absolutestereochemistry unknown. Enantiomer of Ex. 162(−)-8-cyclopentyl-2-{[2,2-dimethyl-1-(methylsulfonyl)piperidin-4-yl]amino}-6-(2-hydroxyethyl)pyrido[2,3-d]pyrimidin- 7(8H)-one 164 (A)

406 ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.41-7.39 (d, 1H), 6.37(br s, 1H), 5.54 (br s, 1H), 5.40-5.25 (m, 1H), 4.05- 3.95 (m, 1H),3.83-3.81 (m, 2H), 3.00- 2.90 (m, 2H), 2.85 (s, 3H), 2.75-2.60 (m, 2H),2.24-2.21 (m, 2H), 1.90-1.85 (m, 2H), 1.73-1.68 (m, 5H), 1.42-1.25 (m,3H). 8-cyclohexyl-2-{[1-(methylsulfonyl)-piperidin-4-yl]amino}pyrido[2,3- d]pyrimidin-7(8H)-one 165 (A)

486 [M + Na]⁺ ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.50 (s, 1H), 7.50(s, 1H), 7.35 (br s, 1H), 5.49 (br s, 1H), 4.28 (br t, J = 5.0 Hz, 1H),3.95 (br d, J = 6.5 Hz, 1H), 3.72- 3.56 (m, 4H), 2.96-2.86 (m, 5H), 2.61(t, J = 6.5 Hz, 2H), 2.04 (br dd, J = 3.1, 13.2 Hz, 2H), 1.85-1.76 (m,2H), 1.75-1.59 (m, 9H), 1.58-1.45 (m, 3H)8-cycloheptyl-6-(2-hydroxyethyl)-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}- pyrido[2,3-d]pyrimidin-7(8H)-one166 (F)

463 ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.56 (s, 1H), 6.75 (br s,1H), 6.10- 5.92 (m, 1H), 5.67-5.07 (m, 2H), 4.03 (br s, 1H), 3.79 (br s,2H), 3.56-3.40 (m, 2H), 2.95 (br s, 2H), 2.84 (s, 3H), 2.77- 2.56 (m,1H), 2.43-2.30 (m, 1H), 2.20 (d, J = 10.0 Hz, 2H), 2.11-2.02 (m, 1H),1.98-1.84 (m, 3H), 1.71 (m, 2H), 1.59 (m, 1H), 0.76 (d, J = 7.0 Hz, 3H)[α]_(D) ²² +24.7 (c 0.2, DMSO) Single enantiomer, absolutestereochemistry known. 2-(8-[(1S,2R)-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetamide 167 (A)

422 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.49 (s, 1H), 7.51 (s, 1H),7.27 (d, J = 7.1 Hz, 1H), 6.14 (quin, J = 8.4 Hz, 1H), 4.47 (br s, 1H),4.26 (d, J = 3.3 Hz, 1H), 3.89-4.03 (m, 1H), 3.62 (d, J = 12.1 Hz, 2H),2.88-2.96 (m, 3H), 2.87 (s, 3H), 2.14-2.30 (m, 2H), 2.04 (s, 3H), 1.88-2.03 (m, 3H), 1.58-1.74 (m, 4H) [α]_(D) ²² −14.8 (c 0.1, CHCl₃) 99% ee;absolute stereochemistry unknown. Enantiomer of Ex. 168(−)-8-[(1R*,3R*)-3-hydroxycyclopentyl]- 6-methyl-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one168 (A)

422 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.49 (br s, 1H), 7.51 (br s,1H), 7.27 (br s, 1H), 6.14 (br s, 1H), 4.48 (br s, 1H), 4.26 (br s, 1H),3.96 (br s, 1H), 3.62 (d, J = 10.0 Hz, 2H), 2.92 (br s, 3H), 2.87 (br s,3H), 2.22 (br s, 2H), 2.04 (br s, 6H), 1.65 (d, J = 9.0 Hz, 4H) [α]_(D)²² +12.1 (c 0.1, CHCl₃) 99% ee; absolute stereochemistry unknown.Enantiomer of Ex. 167 (+)-8-[(1R*,3R*)-3-hydroxycyclopentyl]-6-methyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 169 (D)

442 ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.68 (s, 1H), 6.40-6.22(m, 1H), 5.73-5.27 (m, 1H), 4.72 (br s, 1H), 4.03 (br s, 1H), 3.80 (brd, J = 12.0 Hz, 2H), 3.85-3.71 (m, 1H), 3.02-2.91 (m, 2H), 2.84 (s, 3H),2.56 (br s, 1H), 2.46 (dtd, J = 4.6, 8.5, 12.7 Hz, 1H), 2.32-2.07 (m,4H), 1.88 (br t, J = 11.2 Hz, 1H), 1.74 (br d, J = 12.5 Hz, 3H) [α]_(D)²² +9.5 (c 1.9, CHCl₃) 99% ee; absolute stereochemistry unknown.Enantiomer of Ex. 170 (+)-6-chloro-8-[(1R*,3R*)-3-hydroxycyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 170 (D)

¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.68 (s, 1H), 6.40-6.21 (m,1H), 5.66-5.27 (m, 1H), 4.72 (br s, 1H), 4.03 (br s, 1H), 3.80 (br d, J= 12.3 Hz, 2H), 3.02-2.88 (m, 2H), 2.84 (s, 3H), 2.56 (br s, 1H), 2.47(dtd, J = 4.5, 8.6, 12.9 Hz, 1H), 2.32-2.07 (m, 4H), 1.88 (br t, J =11.3 Hz, 1H), 1.94-1.84 (m, 1H), 1.81-1.67 (m, 3H) [α]_(D) ²² −9.66 (c2.9, CHCl₃) 99% ee; absolute stereochemistry unknown. Enantiomer of Ex.169 (−)-6-chloro-8-[(1R*,3R*)-3- hydroxycyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one171 (J)

472 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.58 (s, 1H), 7.69 (s, 1H),7.52 (d, J = 5.9 Hz, 1H), 6.18-6.09 (m, 1H), 6.21 (tt, J = 4.3, 57.1 Hz,1H), 4.47 (br s, 1H), 4.32 (br s, 1H), 3.97 (br s, 1H), 3.62 (d, J =11.7 Hz, 2H), 3.13-2.98 (m, 2H), 2.96-2.90 (m, 2H), 2.88 (s, 3H), 2.21(br s, 2H), 1.99 (br s, 3H), 1.77-1.55 (m, 4H) ¹⁹F NMR (376 MHz,DMSO-d₆) δ = −114.4 (td, J = 17.2, 57.2 Hz, 1F) [α]_(D) ²² +13.9 (c 0.1,MeOH) ~99% ee; absolute stereochemistry unknown.(+)-6-(2,2-difluoroethyl)-8-[(1R*,3R*)-3- Enantiomer of Ex. 172hydroxycyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 172 (J)

472 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.58 (s, 1H), 7.69 (s, 1H),7.52 (br s, 1H), 6.19-6.09 (m, 1H), 6.21 (tt, J = 4.6, 57.2 Hz, 1H),4.47 (br s, 1H), 3.97 (br s, 1H), 3.69-3.54 (m, 2H), 3.05 (dt, J = 4.5,17.2 Hz, 2H), 2.96-2.88 (m, 2H), 2.88 (s, 3H), 2.31-2.14 (m, 2H),2.07-1.88 (m, 4H), 1.77-1.58 (m, 4H) ¹⁹F NMR (376 MHz, DMSO-d₆) δ =−114.4 (td, J = 17.7, 56.1 Hz, 1F) [α]_(D) ²² −5.1 (c 0.1, MeOH) >99%ee; absolute stereochemistry unknown. Enantiomer of Ex. 171(−)-6-(2,2-difluoroethyl)-8-[(1R*,3R*)-3- hydroxycyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one173 (A)

444 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.34 (d, J = 1.0Hz, 1H), 5.83-5.70 (m, 1H), 5.26 (br s, 1H), 5.00 (d, J = 5.5 Hz, 1H),4.01 (br s, 1H), 3.79 (d, J = 10.3 Hz, 2H), 2.95 (t, J = 11.4 Hz, 2H),2.83 (s, 3H), 2.47-2.28 (m, 2H), 2.20 (dd, J = 4.1, 12.9 Hz, 2H), 2.16(s, 3H), 2.06- 1.86 (m, 3H), 1.71 (dd, J = 6.5, 12.3 Hz, 3H) [α]_(D) ²²+16.7 (c 0.1, MeOH) 98% ee; Single enantiomer, absolute stereochemistryknown 8-[(1R,2R)-2-hydroxycyclopentyl]-6-methyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin- 7(8H)-one 174 (A)

444 ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.45 (d, J = 9.3 Hz, 1H),6.36 (d, J = 9.3 Hz, 1H), 5.73 (t, J = 8.5 Hz, 1H), 5.52-5.30 (m, 1H),4.10-3.89 (m, 1H), 3.82 (t, J = 10.3 Hz, 2H), 3.01-2.86 (m, 2H), 2.83(s, 3H), 2.33-2.13 (m, 3H), 2.09-1.96 (m, 2H), 1.96-1.80 (m, 2H),1.75-1.62 (m, 3H), 1.18 (s, 3H) [α]_(D) ²² +7.28 (c 2.06, CHCl₃) 99% ee;Single enantiomer, absolute stereochemistry known. Enantiomer of Ex. 28-[(1S,2S)-2-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one175 (D)

456 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.67- 8.57 (m, 1H), 8.09 (s, 1H),8.06-7.73 (m, 1H), 5.90 (t, J = 7.9 Hz, 1H), 4.48-4.33 (m, 1H),4.05-3.82 (m, 1H), 3.57 (br s, 2H), 2.88 (s, 4H), 2.86-2.76 (m, 1H),2.45-2.29 (m, 1H), 2.17 (d, J = 9.2 Hz, 2H), 2.03-1.77 (m, 4H),1.73-1.40 (m, 3H), 0.87-1.07 [α]_(D) ²² +15.4 (c 0.1 MeOH) 99% ee;Single enantiomer, absolute stereochemistry known. Enantiomer of Ex. 96-chloro-8-[(1S,2S)-2-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one176 (E)

472 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.73 (s, 1H), 8.03 (s, 1H),7.76 (br s, 1H), 6.83 (t, J = 56.0 Hz, 1H), 5.87 (t, J = 8.3 Hz, 1H),4.11-3.96 (m, 2H), 3.62 (t, J = 11.6 Hz, 2H), 2.97-2.89 (m, 2H), 2.87(s, 3H), 2.26-2.14 (m, 1H), 2.14- 1.82 (m, 5H), 1.79-1.51 (m, 3H), 1.03(s, 3H) ¹⁹F NMR (376 MHz, DMSO-d₆) δ = −125.2 to −113.7 (m, 2F) [α]_(D)²² +24.7 (c 0.2, CHCl₃) >99% ee; Single enantiomer, absolute6-(difluoromethyl)-8-[(1S,2S)-2- stereochemistry known.hydroxy-2-methylcyclopentyl]-2-{[1- Enantiomer of Ex. 10(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one177 (I)

479 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.91- 8.71 (m, 1H), 8.12-7.64 (m, 1H),5.87 (t, J = 8.4 Hz, 1H), 4.44-4.22 (m, 1H), 3.91 (br s, 1H), 3.66-3.49(m, 2H), 2.95-2.79 (m, 6H), 2.38 (s, 3H), 2.27 (s, 3H), 2.18 (d, J = 9.4Hz, 2H), 2.02-1.89 (m, 3H), 1.85 (br s, 2H), 1.72-1.59 (m, 2H), 1.07-0.94 (m, 3H) [α]_(D) ²² −36.5 (c 0.1, MeOH) 99% ee; absolutestereochemistry unknown. Enantiomer of Ex. 178(−)-6-acetyl-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-5-methyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 178 (I)

479 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.86- 8.77 (m, 1H), 8.08-7.74 (m, 1H),5.94- 5.80 (m, 1H), 4.40-4.27 (m, 1H), 4.13- 3.82 (m, 1H), 3.64-3.51 (m,2H), 2.94- 2.82 (m, 5H), 2.38 (s, 3H), 2.27 (s, 3H), 2.18 (d, J = 10.0Hz, 2H), 2.07-1.90 (m, 3H), 1.85 (br s, 2H), 1.65 (br s, 3H), 0.99 (brs, 3H) [α]_(D) ²² +27.0 (c 0.1, MeOH) 99% ee; absolute stereochemistryunknown. Enantiomer of Ex. 177 (+)-6-acetyl-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-5-methyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 179 (F)

501 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.45 (s, 1H), 7.58 (s, 1H),6.61 (br s, 1H), 5.79 (br s, 1H), 5.58 (br s, 1H), 5.38 (br s, 1H), 3.99(br s, 1H), 3.89-3.76 (m, 2H), 3.54-3.38 (m, 2H), 3.02-2.87 (m, 2H),2.83 (s, 4H), 2.35-2.13 (m, 4H), 2.06- 1.82 (m, 4H), 1.75-1.69 (m, 2H),1.15 (s, 3H) [α]_(D) ²² −11.81 (c 0.11, MeOH)) 99% ee; absolutestereochemistry unknown. Enantiomer of Ex. 180(−)-2-(8-[(1R*,2R*)-2-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)acetamide 180 (F)

501 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.45 (s, 1H), 7.58 (s, 1H),6.60 (br s, 1H), 5.82 (br s, 1H), 5.53 (br s, 1H), 5.33 (br s, 1H), 3.98(br s, 1H), 3.83 (d, J = 10.5 Hz, 2H), 3.55-3.41 (m, 2H), 3.00-2.72 (m,6H), 2.37-2.14 (m, 4H), 2.07-1.83 (m, 4H), 1.77-1.65 (m, 2H), 1.15 (s,3H) [α]_(D) ²² +10.90 (c 0.11, MeOH) 99% ee; absolute stereochemistryunknown. Enantiomer of Ex. 179 (+)-2-(8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)acetamide 181 (A)

490 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.51 (s, 1H), 7.53 (s, 1H),7.40 (d, J = 7.7 Hz, 1H), 5.94-5.80 (m, 1H), 4.09 (d, J = 7.2 Hz, 1H),4.04 (s, 1H), 3.92- 3.76 (m, 2H), 3.43-3.27 (m, 2H), 2.29- 2.11 (m, 2H),2.11-2.00 (m, 1H), 2.03 (s, 3H), 2.00-1.81 (m, 3H), 1.77-1.51 (m, 3H),0.99 (s, 3H) ¹⁹F NMR (376 MHz, DMSO-d₆, 80° C.) δ = −75.41 (s, 3F)[α]_(D) ²² −11.6 (c 0.3, CHCl₃) 99% ee; absolute stereochemistryunknown. (−)-8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 182methylcyclopentyl]-6-methyl-2-({1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 182 (A)

490 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.51 (s, 1H), 7.53 (s, 1H),7.41 (d, J = 7.0 Hz, 1H), 6.97 (br s, 1H), 5.87 (t, J = 8.3 Hz, 1H),4.15-4.06 (m, 1H), 4.05 (s, 1H), 3.93-3.76 (m, 2H), 3.35 (q, J = 10.8Hz, 2H), 2.28-2.11 (m, 2H), 2.11-2.00 (m, 1H), 2.03 (s, 3H), 2.00- 1.81(m, 3H), 1.76-1.46 (m, 3H), 0.99 (s, 3H) ¹⁹F NMR (376 MHz, DMSO-d₆, 80°C.) δ = −75.41 (s, 3F) [α]_(D) ²² +5.82 (c 0.33, CHCl₃) 99% ee; absolutestereochemistry (+)-8-[(1R*,2R*)-2-hydroxy-2- unknown.methylcyclopentyl]-6-methyl-2-({1- Enantiomer of Ex. 181[(trifluoromethyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 183 (A)

423 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.55 (s, 1H), 7.64 (d, J = 9.3Hz, 1H), 7.42 (br s, 1H), 6.48 (br s, 2H), 6.19 (d, J = 9.2 Hz, 1H),5.85 (t, J = 8.4 Hz, 1H), 4.03 (s, 1H), 3.97-3.82 (m, 1H), 3.53 (t, J =10.6 Hz, 2H), 2.73 (t, J = 11.6 Hz, 2H), 2.62-2.52 (m, 1H), 2.28-2.13(m, 1H), 2.13-1.80 (m, 5H), 1.75-1.56 (m, 3H), 1.02 (s, 3H) [α]_(D) ²²−24.1 (c 0.1, MeOH) 99% ee; absolute stereochemistry unknown(−)-4-({8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 184methylcyclopentyl]-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)piperidine-1-sulfonamide 184 (A)

423 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.55 (s, 1H), 7.64 (d, J = 9.3Hz, 1H), 7.42 (br s, 1H), 6.49 (br s, 2H), 6.19 (d, J = 9.2 Hz, 1H),5.85 (t, J = 8.3 Hz, 1H), 4.03 (s, 1H), 3.98-3.82 (m, 1H), 3.53 (t, J =10.6 Hz, 2H), 2.73 (t, J = 11.6 Hz, 2H), 2.62-2.52 (m, 1H), 2.28-2.14(m, 1H), 2.12-1.79 (m, 5H), 1.77-1.51 (m, 3H), 1.02 (s, 3H) [α]_(D) ²²+18.0 (c 0.1, MeOH) 95% ee; absolute stereochemistry unknown(+)-4-({8-[(1R*,2R*)-2-hydroxy-2- Enantiomer of Ex. 183methylcyclopentyl]-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)piperidine-1-sulfonamide 185 (A)

452 ¹H NMR (400 MHz, CDCl₃) δ = 8.47 (s, 1H), 7.49 (s, 1H), 5.82-5.73(m, 1H), 5.44 (br s, 1H), 4.57 (s, 2H), 4.02 (br d, J = 7.8 Hz, 1H),3.82 (br t, J = 10.8 Hz, 2H), 2.97-2.89 (m, 2H), 2.83 (s, 3H), 2.31-2.18(m, 3H), 2.12-1.78 (m, 5H), 1.74-1.64 (m, 2H), 1.17 (s, 3H) [α]_(D) ²²−20.7 (c 2, CHCl₃) 99% ee; absolute stereochemistry unknown Enantiomerof Ex. 186 (−)-6-(hydroxymethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 186 (A)

452 ¹H NMR (400 MHz, CDCl₃) δ = 8.47 (s, 1H), 7.49 (s, 1H), 5.77 (br t,J = 7.9 Hz, 1H), 5.41 (br s, 1H), 4.57 (br s, 2H), 3.99 (br s, 1H),3.87-3.68 (m, 2H), 2.99- 2.89 (m, 2H), 2.83 (s, 3H), 2.29-2.17 (m, 3H),2.13-1.77 (m, 5H), 1.69 (br s, 2H), 1.17 (s, 3H) [α]_(D) ²² +4.3 (c 2,CHCl₃) 99% ee; absolute stereochemistry unknown Enantiomer of Ex. 185(+)-6-(hydroxymethyl)-8-[(1R*,2R*)-2-hydroxy-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 187 (E)

473 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.73 (s, 1H), 8.03 (s, 1H), 7.72 (d, J= 3.7 Hz, 1H), 7.01-6.65 (m, 1H), 6.48 (br s, 2H), 5.96-5.71 (m, 1H),4.07 (s, 1H), 3.95 (d, J = 7.1 Hz, 1H), 3.55 (t, J = 10.4 Hz, 2H), 2.76(t, J = 11.7 Hz, 2H), 2.60-2.54 (m, 1H), 2.27-2.16 (m, 1H), 2.14-1.95(m, 3H), 1.95-1.84 (m, 2H), 1.77-1.72 (m, 1H), 1.71-1.54 (m, 2H), 1.04(s, 3H) [α]_(D) ²² −18.3 (c 0.4, CHCl₃) 91% ee; absolute stereochemistryunknown (−)-4-({6-(difluoromethyl)-8-[(1R*,2R*)- Enantiomer of Ex. 1882-hydroxy-2-methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)piperidine-1-sulfonamide188 (E)

473 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.73 (s, 1H), 8.03 (s, 1H), 7.72 (d, J= 3.7 Hz, 1H), 7.01-6.65 (m, 1H), 6.48 (br s, 2H), 5.96-5.71 (m, 1H),4.07 (s, 1H), 3.95 (d, J = 7.1 Hz, 1H), 3.55 (t, J = 10.4 Hz, 2H), 2.76(t, J = 11.7 Hz, 2H), 2.60-2.54 (m, 1H), 2.27-2.16 (m, 1H), 2.14-1.95(m, 3H), 1.95-1.84 (m, 2H), 1.77-1.72 (m, 1H), 1.71-1.54 (m, 2H), 1.04(s, 3H) [α]_(D) ²² +15.8 (c 0.1, CHCl₃) 99% ee; absolute stereochemistryunknown (+)-4-({6-(difluoromethyl)-8-[(1R*,2R*)- Enantiomer of Ex. 1872-hydroxy-2-methylcyclopentyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)piperidine-1-sulfonamide189 (A)

462 [M − H₂O + 1]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.45 (d, J= 9.5 Hz, 1H), 6.34 (br d, J = 9.3 Hz, 1H), 5.81-5.54 (m, 2H), 3.99 (brs, 1H), 3.88-3.77(m, 2H), 3.65 (br s, 1H), 3.07 (s, 2H), 3.02-2.91 (m,2H), 2.83 (br s, 1H), 2.31-2.12 (m, 3H), 2.06- 1.83 (m, 5H), 1.76-1.56(m, 2H), 1.45 (s, 6H), 1.16 (s, 3H) 99% ee; Single enantiomer, absolutestereochemistry known 8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-({1-[(2-hydroxy-2-methylpropyl)sulfonyl]piperidin-4-yl}amino)pyrido[2,3-d]pyrimidin-7(8H)- one 190 (A)

500 ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.45 (d, J = 9.3 Hz, 1H),6.35 (d, J = 9.3 Hz, 1H), 5.74 (br s, 1H), 5.46 (br s, 1H), 4.44 (s,2H), 4.12-3.97 (m, 1H), 3.94-3.82 (m, 2H), 3.36-3.24 (m, 1H), 3.24 (s,3H), 3.20 (d, J = 2.8 Hz, 1H), 2.94-2.73 (m, 1H), 2.31-2.16 (m, 3H),2.05-1.97 (m, 2H), 1.97-1.87 (m, 1H), 1.87-1.78 (m, 1H), 1.77-1.63 (m,2H), 1.17 (s, 3H) Single enantiomer, absolute stereochemistry known8-[(1R,2R)-2-hydroxy-2- methylcyclopentyl]-2-[(1-{[(methylsulfonyl)methyl]sulfonyl}piperi-din-4-yl)amino]pyrido[2,3-d]pyrimidin- 7(8H)-one 191 (D)

474 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.65 (s, 1H), 8.20 (d, J = 5.5 Hz,1H), 8.12- 7.83 (m, 1H), 5.87 (t, J = 8.0 Hz, 1H), 5.41-4.82 (m, 1H),4.48 (s, 1H), 4.28- 3.95 (m, 1H), 3.81 (t, J = 11.6 Hz, 1H), 3.70 (d, J= 11.9 Hz, 1H), 3.20-2.99 (m, 2H), 2.92 (s, 3H), 2.48-2.33 (m, 1H),2.23-2.07 (m, 1H), 2.06-1.89 (m, 2H), 1.88-1.73 (m, 3H), 1.68 (d, J =7.0 Hz, 1H), 1.01-0.89 (m, 3H) ¹⁹F NMR (565 MHz, DMSO-d₆) δ = −201.1 (brs, 1F) (−)-6-chloro-2-{[(3R*,4S*)-3-fluoro-1- [α]_(D) ²² −99.6 (c 0.1,CHCl₃) (methylsulfonyl)piperidin-4-yl]amino}-8- 98% de; Singlediastereomer, absolute [(1R,2R)-2-hydroxy-2- stereochemistry known R,Rat methylcyclopentyl]pyrido[2,3- cyclopentyl chiral centers, relatived]pyrimidin-7(8H)-one stereochemistry known to be cis at piperidinechiral centers. Diastereomer of Ex. 192 192 (D)

474 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.65 (d, J = 7.9 Hz, 1H), 8.11 (br s,1H), 7.88 (br s, 1H), 5.97-5.74 (m, 1H), 5.13-4.84 (m, 1H), 4.55-4.32(m, 1H), 4.29-4.02 (m, 1H), 3.96-3.78 (m, 1H), 3.67 (d, J = 11.9 Hz,1H), 3.24-2.97 (m, 2H), 2.93 (d, J = 7.5 Hz, 3H), 2.38 (br s, 1H), 2.24-2.09 (m, 1H), 2.04-1.75 (m, 5H), 1.68 (d, J = 8.8 Hz, 1H), 0.98 (d, J =7.5 Hz, 3H) ¹⁹F NMR (565 MHz, DMSO-d₆) δ = −200.8 (br s, 1F)(+)-6-chloro-2-{[(3R*,4S*)-3-fluoro-1- [α]_(D) ²² +8.9 (c 0.2, CHCl₃)(methylsulfonyl)piperidin-4-yl]amino}-8- 99% de; Single diastereomer,absolute [(1R,2R)-2-hydroxy-2- stereochemistry known R,R atmethylcyclopentyl]pyrido[2,3- cyclopentyl chiral centers, relatived]pyrimidin-7(8H)-one stereochemistry known to be cis at piperidinechiral centers. Diastereomer of Ex. 191 193 (A)

436 ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 1H), 7.45 (d, J = 9.3 Hz,1H), 6.35 (d, J = 9.3 Hz, 1H), 5.75 (br s, 1H), 5.48 (br s, 1H), 3.99(br s, 1H), 3.87-3.76 (m, 2H), 2.99-2.90 (m, 2H), 2.87-2.77 (m, 4H),2.22 (d, J = 12.3 Hz, 3H), 2.09-1.98 (m, 2H), 1.95-1.87 (m, 1H), 1.78(dd, J = 6.7, 12.4 Hz, 1H), 1.73-1.65 (m, 3H), 1.57-1.45 (m, 1H), 1.27(qd, J = 7.3, 14.1 Hz, 1H), 0.87 (t, J = 7.4 Hz, 3H) [α]_(D) ²² −5.26 (c0.5, CHCl₃) 99% ee; absolute stereochemistry(−)-(8-[(1R*,2R*)-2-ethyl-2- unknown hydroxycyclopentyl]-2-{[1-Enantiomer of Ex. 194 (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 194 (A)

436 ¹H NMR (400 MHz, CDCl₃) δ = 8.42 (s, 1H), 7.45 (d, J = 9.3 Hz, 1H),6.35 (d, J = 9.3 Hz, 1H), 5.75 (br s, 1H), 5.46 (br s, 1H), 3.98 (br s,1H), 3.82 (t, J = 10.8 Hz, 2H), 2.98-2.89 (m, 2H), 2.87-2.72 (m, 4H),2.22 (d, J = 11.8 Hz, 3H), 2.08- 1.99 (m, 2H), 1.96-1.85 (m, 1H), 1.78(dd, J = 6.7, 12.4 Hz, 1H), 1.72-1.63 (m, 3H), 1.56-1.47 (m, 1H),1.32-1.23 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H) [α]_(D) ²² +2.73 (c 0.5,CHCl₃) 99% ee; absolute stereochemistry (+)-(8-[(1R*,2R*)-2-ethyl-2-unknown hydroxycyclopentyl]-2-{[1- Enantiomer of Ex. 193(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one195 (D)

470 ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.69 (s, 1H), 5.86 (br s,1H), 5.49 (br s, 1H), 3.97 (br s, 1H), 3.89-3.77 (m, 2H), 2.99-2.88 (m,2H), 2.83 (s, 3H), 2.66 (br s, 1H), 2.35-2.17 (m, 3H),2.10- 2.03 (m,2H), 1.98-1.88 (m, 1H), 1.77 (dd, J = 6.3, 12.5 Hz, 2H), 1.60 (s, 2H),1.48 (dd, J = 7.4, 13.9 Hz, 1H), 1.27 (qd, J = 7.2, 14.2 Hz, 1H), 0.87(t, J = 7.4 Hz, 3H) [α]_(D) ²² −2.08 (c 0.4, CHCl₃) 99% ee; absolutestereochemistry (−)-6-chloro-8-[(1R*,2R*)-2-ethyl-2- unknownhydroxycyclopentyl]-2-{[1- Enantiomer of Ex. 196(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one196 (D)

470 ¹H NMR (400 MHz, CDCl₃) δ = 8.43 (s, 1H), 7.69 (s, 1H), 5.87 (br s,1H), 5.50 (br s, 1H), 3.97 (br s, 1H), 3.89-3.73 (m, 2H), 3.00-2.88(m,2H), 2.86-2.80 (m, 3H), 2.66 (br s, 1H), 2.36-2.16 (m, 3H), 2.12-2.02(m, 2H), 1.99-1.87 (m, 1H), 1.77 (dd, J = 7.0, 12.3 Hz, 2H), 1.61 (s,2H), 1.54-1.44 (m, 1H), 1.27 (qd, J = 7.3, 14.1 Hz, 1H), 0.87 (t, J =7.2 Hz, 3H) [α]_(D) ²² +1.66 (c 0.4, CHCl₃) 99% ee; absolutestereochemistry unknown (+)-6-chloro-8-[(1R*,2R*)-2-ethyl-2- Enantiomerof Ex. 195 hydroxycyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 197 (A)

438 ¹H NMR (400 MHz, CDCl₃) δ = 8.41 (s, 1H), 7.37 (s, 1H), 6.06 (br s,1H), 5.51 (d, J = 7.8 Hz, 1H), 4.65 (br s, 1H), 4.38- 4.26 (m, 2H), 4.04(br s, 1H), 3.91 (d, J = 9.0 Hz, 1H), 3.83 (t, J = 11.2 Hz, 2H),2.96-2.87 (m, 2H), 2.83 (s, 3H), 2.29- 2.14 (m, 5H), 1.77-1.68 (m, 2H),1.16 (s, 3H) [α]_(D) ²² −20.5 (c 0.12, MeOH) 99% ee; absolutestereochemistry unknown Enantiomer of Ex. 198(−)-8-[(3R*,4S*)-4-hydroxy-4- methyltetrahydrofuran-3-yl]-6-methyl-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one 198 (A)

438 ¹H NMR (400 MHz, CDCl₃) δ = 8.41 (s, 1H), 7.37 (d, J = 1.0 Hz, 1H),6.06 (br s, 1H), 5.41 (br s, 1H), 4.65 (br s, 1H), 4.29 (t, J = 9.0 Hz,2H), 4.10-3.99 (m, 1H), 3.91 (d, J = 8.8 Hz, 1H), 3.87-3.79 (m, 2H),2.96-2.88 (m, 2H), 2.83 (s, 3H), 2.29-2.14 (m, 5H), 1.70 (m, J = 12.8Hz, 2H), 1.16 (s, 3H) [α]_(D) ²² +11.21 (c 0.116, MeOH) 99% ee; absolutestereochemistry unknown Enantiomer of Ex. 197(+)-8-[(3R*,4S*)-4-hydroxy-4- methyltetrahydrofuran-3-yl]-6-methyl-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one 199 (A)

458 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.36 (d, J = 1.3Hz, 1H), 6.12-5.92 (m, 1H), 5.32 (br s, 1H), 4.43 (br d, J = 6.3 Hz,1H), 4.04 (br d, J = 7.3 Hz, 1H), 3.88-3.50 (m, 3H), 2.98 (br d, J =14.8 Hz, 2H), 2.88-2.78 (m, 3H), 2.57-2.41 (m, 3H), 2.28 (td, J = 7.6,12.7 Hz, 1H), 2.23-2.13 (m, 5H), 2.08-1.95 (m, 1H), 1.78-1.68 (m, 2H),0.80 (d, J = 7.0 Hz, 3H) [α]_(D) ²² −14.5 (c 0.2, MeOH) 99% ee; absolutestereochemistry unknown Enantiomer of Ex. 200(−)-8-[(1R*,2S*,4R*)-4-hydroxy-2- methylcyclopentyl]-6-methyl-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one200 (A)

458 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.39 (s, 1H), 7.36 (d, J = 1.3Hz, 1H), 6.13-5.90 (m, 1H), 5.29 (br s, 1H), 4.42 (br t, J = 6.4 Hz,1H), 4.04 (br s, 1H), 3.88-3.45 (m, 3H), 2.96 (br s, 2H), 2.83 (s, 3H),2.55- 2.39 (m, 3H), 2.36-2.24 (m, 1H), 2.17 (d, J = 1.3 Hz, 5H),2.09-1.95 (m, 1H), 1.74-1.65 (m, 2H), 0.81 (d, J = 7.0 Hz, 3H) [α]_(D)²² +18.1 (c 0.1, MeOH) 99% ee; absolute stereochemistry unknownEnantiomer of Ex. 199 (+)-8-[(1R*,2S*,4R*)-4-hydroxy-2-methylcyclopentyl]-6-methyl-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 201 (A)

422 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.56 (s, 1H), 7.65 (d, J = 9.3 Hz,1H), 7.47 (d, J = 4.8 Hz, 1H), 6.21 (d, J = 9.2 Hz, 1H), 5.84-5.63 (m,1H), 4.23 (d, J = 3.7 Hz, 1H), 4.13 (br s, 1H), 4.00-3.88 (m, 1H),3.70-3.50 (m, 2H), 2.95-2.89 (m, 3H), 2.89-2.79 (m, 3H), 2.31-2.17-(m,2H), 2.03-1.86-(m, 2H), 1.77-1.56 (m, 3H), 0.84 (d, J = 6.8 Hz, 3H)[α]_(D) ²² −17.2 (c 0.1, MeOH) 99% ee; absolute stereochemistry unknownEnantiomer of Ex. 202 (−)-8-[(1R*,2S*,3R*)-3-hydroxy-2-methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 202 (A)

422 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.56 (s, 1H), 7.65 (d, J = 9.3 Hz,1H), 7.48 (br s, 1H), 6.21 (d, J = 9.3 Hz, 1H), 5.87-5.63 (m, 1H), 4.23(d, J = 3.7 Hz, 1H), 4.13 (br s, 1H), 3.99-3.83 (m, 1H), 3.70-3.45 (m,2H), 2.98-2.788 (m, 6H), 2.29-2.14 (m, 2H), 2.03-1.97 (m, 2H), 1.97-1.86(m, 1H), 1.76-1.56 (m, 3H), 0.84 (d, J = 6.8 Hz, 3H) [α]_(D) ²² +19.9 (c0.1, MeOH) 99% ee; absolute stereochemistry unknown Enantiomer of Ex.201 (+)-8-[(1R*,2S*,3R*)-3-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one203 (D)

456 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.61 (br s, 1H), 8.08 (s, 1H),8.05-7.69 (m, 1H), 5.79 (br s, 1H), 4.53 (br s, 1H), 4.09 (br s, 1H),4.04-3.74 (m, 1H), 3.57 (d, J = 10.5 Hz, 2H), 2.97-2.73 (m, 6H), 2.18(br s, 2H), 1.96 (br s, 3H), 1.78- 1.46 (m, 3H), 0.81 (d, J = 6.8 Hz,3H) [α]_(D) ²² −9.5 (c 0.1, MeOH) Single enantiomer, absolutestereochemistry unknown Made from Ex. 201(−)-6-chloro-8-[(1R*,2S*,3R*)-3- hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one204 (E)

472 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.64 (s, 1H), 7.94 (s, 1H),7.72 (br s, 1H), 6.94-6.47 (m, 1H), 5.65 (d, J = 6.7 Hz, 1H), 4.18 (d, J= 3.3 Hz, 1H), 4.05 (br s, 1H), 3.87 (br s, 1H), 3.54 (dd, J = 4.40,11.49 Hz, 2H), 2.87-2.75 (m, 6H), 2.14 (br s, 2H), 1.99-1.80 (m, 3H),1.70-1.46 (m, 3H), 0.76 (d, J = 6.8 Hz, 3H) ¹⁹F NMR (376 MHz, DMSO-d₆) δ= −118.6 to −114.9 (m, 2F) [α]_(D) ²² −29.9 (c 0.4, MeOH) Singleenantiomer, absolute stereochemistry unknown Made from Ex. 201(−)-6-(difluoromethyl)-8- Enantiomer of Ex. 205[(1R*,2S*,3R*)-3-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one205 (E)

472 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.73 (s, 1H), 8.04 (s, 1H), 7.83 (brs, 1H), 7.04-6.55 (m, 1H), 5.84-5.63 (m, 1H), 4.27 (d, J = 3.8 Hz, 1H),4.14 (br s, 1H), 3.96 (br s, 1H), 3.64 (dd, J = 4.03, 12.35 Hz, 2H),2.96-2.82 (m, 6H), 2.23 (br s, 2H), 2.07-1.91 (m, 3H), 1.77-1.55 (m,3H), 0.86 (d, J = 6.8 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ = −119.9 to−118.0 (m, 2F). [α]_(D) ²² +19.6 (c 0.5, MeOH) Single enantiomer,absolute stereochemistry unknown Made from Ex. 202(+)-6-(difluoromethyl)-8- Enantiomer of Ex. 204[(1R*,2S*,3R*)-3-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one206 (J)

486 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.60 (br s, 1H), 7.88 (br s,1H), 7.73 (s, 1H), 6.22 (tt, J = 4.6, 57.1 Hz, 1H), 5.75 (br s, 1H),4.51 (br s, 1H), 4.09 (br s, 1H), 4.05-3.74 (m, 1H), 3.65-3.51 (m, 2H),3.04 (dt, J = 4.2, 17.1 Hz, 2H), 2.89 (s, 3H), 2.88-2.77 (m, 3H), 2.20(br s, 2H), 1.95 (br s, 3H), 1.78-1.45 (m, 3H), 0.80 (d, J = 6.8 Hz, 3H)[α]_(D) ²² −10.3 (c 0.1, MeOH) Single enantiomer, absolutestereochemistry unknown Made from Ex. 201 (−)-6-(2,2-difluoroethyl)-8-[(1R*,2S*,3R*)-3-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one207 (A)

422 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.57 (s, 1H), 7.69 (d, J = 9.2 Hz,1H), 7.56 (d, J = 6.6 Hz, 1H), 6.19 (d, J = 9.2 Hz, 1H), 6.16-5.95 (m,1H), 4.96 (d, J = 10.8 Hz, 1H), 4.00-3.73 (m, 2H), 3.63-3.42 (m, 2H),2.91-2.811 (m, 2H), 2.79 (s, 3H), 2.70-2.56 (m, 1H), 2.39-2.29 (m, 1H),1.98-1.85 (m, 2H), 1.82-1.70 (m, 2H), 1.71-1.49 (m, 3H), 0.57 (d, J =7.5 Hz, 3H) [α]_(D) ²² +27.3 (c 0.1, MeOH) 99% ee; absolutestereochemistry unknown Enantiomer of Ex. 208(+)-8-[(1R*,2R*,3S*)-3-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one208 (A)

422 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.67 (s, 1H), 7.79 (d, J = 9.3 Hz,1H), 7.66 (d, J = 6.5 Hz, 1H), 6.29 (d, J = 9.2 Hz, 1H), 6.06-6.24 (m,1H), 5.06 (d, J = 10.5 Hz, 1H), 3.90-4.10 (m, 2H), 3.61 (dd, J = 6.72,10.88 Hz, 2H), 2.91-3.01 (m, 2H), 2.88 (s, 3H), 2.64-2.79 (m, 1H),2.39-2.46 (m, 1H), 1.95-2.06 (m, 2H), 1.78-1.91 (m, 2H), 1.60-1.79 (m,3H), 0.67 (d, J = 7.3 Hz, 3H) [α]_(D) ²² −33.1 (c 0.1, MeOH) 99% ee;absolute stereochemistry unknown Enantiomer of Ex. 207(−)-8-[(1R*,2R*,3S*)-3-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one209 (A)

422 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.47 (s, 1H), 7.56 (d, J = 9.3 Hz,1H), 7.39 (d, J = 6.2 Hz, 1H), 6.10 (d, J = 9.3 Hz, 1H), 5.98 (dt, J =7.15, 10.06 Hz, 1H), 4.24 (d, J = 5.3 Hz, 1H), 4.18-4.07 (m, 1H), 3.97-3.82 (m, 1H), 3.57-3.46 (m, 2H), 2.91- 2.81 (m, 2H), 2.79 (s, 3H),2.14-2.02 (m, 1H), 1.99-1.88 (m, 3H), 1.88-1.76 (m, 1H), 1.66-1.45 (m,2H), 1.45-1.28 (m, 1H), 0.62 (d, J = 7.2 Hz, 3H) [α]_(D) ²² +3.1 (c 0.1,MeOH) 99% ee; absolute stereochemistry unknown Enantiomer of Ex. 210(+)-8-[(1R*,2R*,3R*)-3-hydroxy-2- methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one210 (A)

422 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.56 (s, 1H), 7.66 (d, J = 9.3 Hz,1H), 7.48 (d, J = 7.0 Hz, 1H), 6.20 (d, J = 9.3 Hz, 1H), 6.08 (dt, J =6.91, 10.18 Hz, 1H), 4.33 (d, J = 5.1 Hz, 1H), 4.14-4.28 (m, 1H), 4.05-3.89 (m, 1H), 3.68-3.54 (m, 2H), 2.99- 2.90 (m, 2H), 2.88 (s, 3H),2.26-2.11 (m, 1H), 2.09-1.99 (m, 3H), 1.92 (dtd, J = 2.51, 9.60, 12.41Hz, 1H), 1.74-1.57 (m, 2H), 1.54-1.40 (m, 1H), 0.71 (d, J = 7.2 Hz, 3H)[α]_(D) ²² −5.1 (c 0.1, MeOH) 99% ee; absolute stereochemistry unknown(−)-8-[(1R*,2R*,3R*)-3-hydroxy-2- Enantiomer of Ex. 209methylcyclopentyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 211 (A)

444 [M + Na]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 8.38 (s, 1H), 7.41 (d, J = 9.3Hz, 1H), 6.32 (d, J = 8.8 Hz, 1H), 5.95 (br s, 1H), 5.52 (br s, 1H),4.35 (br s, 1H), 4.05-3.87 (m, 1H), 3.86-3.77 (m, 2H), 3.02-2.85 (m,3H), 2.83 (s, 3H), 2.67 (d, J = 11.3 Hz, 1H), 2.22 (d, J = 12.0 Hz, 2H),1.92-1.69 (m, 8H) [α]_(D) ²² −11.52 (c 0.11, CHCl₃) 98% ee; Singleenantiomer, absolute stereochemistry known Enantiomer of Ex. 38-[(1S,3S)-3-hydroxycyclohexyl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 212 (E)

472 ¹H NMR (700 MHz, DMSO-d₆) δ = 8.78- 8.65 (m, 1H), 8.15 (d, J = 6.4Hz, 1H), 8.06-7.82 (m, 1H), 6.98-6.71 (m, 1H), 6.18-5.49 (m, 1H), 4.49(br s, 1H), 4.13 (br s, 1H), 4.05-3.75 (m, 1H), 3.68-3.48 (m, 2H),3.02-2.73 (m, 6H), 2.24-1.90 (m, 2H), 1.86-1.69 (m, 2H), 1.68-1.44 (m,6H), 1.43-1.31 (m, 1H⁾ [α]_(D) ²² +18.1 (c 0.1, CHCl₃) [Singleenantiomer, absolute stereochemistry known.6-(difluoromethyl)-8-[(1R,3R)-3- hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one213 (F)

479 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.56 (br s, 1H), 7.95-7.68 (m, 1H),7.56 (br s, 1H), 7.34 (br s, 1H), 6.86 (br s, 1H), 6.08-5.60 (m, 1H),4.49 (br s,1H), 4.12 (br s, 1H), 3.83 (br s, 1H), 3.68-3.46 (m, 2H),3.22 (br s, 2H), 2.89 (br s, 3H), 2.84 (br s, 2H), 2.48-2.35 (m, 2H),1.99 (br s, 2H), 1.77-1.32 (m, 8H) [α]_(D) ²² +9.67 (c 0.2, DMSO) 98%ee; absolute stereochemistry unknown Enantiomer of Ex. 214(+)-2-(8-[(1R*3R*)-3- hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)acetamide 214 (F)

479 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.56 (br s, 1H), 7.94-7.70 (m, 1H),7.56 (br s, 1H), 7.34 (br s, 1H), 6.86 (br s, 1H), 6.13-5.62 (m, 1H),4.49 (br s, 1H), 4.12 (br s, 1H), 3.83 (br s, 1H), 3.68-3.50 (m, 2H),3.22 (br s, 2H), 2.89 (br s, 3H), 2.83 (d, J = 8.8 Hz, 2H), 2.48-2.35(m, 2H), 2.13-1.90 (m, 2H), 1.86-1.33 (m, 8H) [α]_(D) ²² −26.33 (c 0.2,DMSO) 98% ee; absolute stereochemistry unknown Enantiomer of Ex. 213(−)-2-(8-[(1R*3R*)-3- hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)acetamide 215 (A)

422 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.58- 8.51 (m, 1H), 7.83-7.74 (m, 1H),7.65 (d, J = 9.3 Hz, 1H), 6.28-6.19 (m, 1H), 5.23-5.08 (m, 1H),4.56-4.43 (m, 1H), 4.41-4.19 (m, 1H), 3.96-3.87 (m, 1H), 3.58-3.48 (m,2H), 3.29-2.89 (m, 4H), 2.88-2.81 (m, 3H), 1.99-1.87 (m, 2H), 1.85-1.77(m, 2H), 1.63-1.47 (m, 4H), 1.30-1.21 (m, 2H)8-(cis-4-hydroxycyclohexyl)-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 216 (A)

436 ¹H NMR (400 MHz, DMSO-d₆) δ = 8.54 (s, 1H), 7.64 (d, J = 9.3 Hz,1H), 7.51 (br s, 1H), 6.17 (br s, 1H), 5.92-5.23 (m, 1H), 4.23 (br s,1H), 4.12 (br s, 1H), 3.93 (br d, J = 7.3 Hz, 1H), 3.65 (br d, J = 12.0Hz, 2H), 3.04-2.80 (m, 6H), 2.79-2.62 (m, 1H), 2.26-1.89 (m, 2H),1.85-1.47 (m, 7H), 0.65 (d, J = 6.5 Hz, 3H) [α]_(D) ²² +12.0 (c 0.3,MeOH) Single enantiomer, absolute stereochemistry known8-[(1S,2S,5R)-5-hydroxy-2- methylcyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one217 (A)

440 ¹H NMR (400 MHz, CDCl₃) δ = 8.41 (s, 1H), 7.46 (d, J = 9.4 Hz, 1H),6.34 (br d, J = 9.1 Hz, 1H), 6.25 (br s, 1H), 5.82- 5.55 (m, 2H), 4.28(br d, J = 2.9 Hz, 1H), 4.04-3.68 (m, 3H), 3.03-2.88 (m, 2H), 2.84 (s,3H), 2.23 (br d, J = 12.1 Hz, 2H), 2.18-2.03 (m, 2H), 1.98-1.75 (m, 5H),1.74-1.69 (m, 2H) [α]_(D) ²² +3.67 (c 0.2, CHCl₃) 99% ee; absolutestereochemistry unknown Enantiomer of Ex. 218(+)-8-[(1S*,2S*,5R*)-2-fluoro-5- hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one218 (A)

440 ¹H NMR (400 MHz, CDCl₃) δ = 8.41 (s, 1H), 7.46 (d, J = 9.3 Hz, 1H),6.33 (br d, J = 8.8 Hz, 2H), 5.87-5.57 (m, 1H), 5.48 (br s, 1H), 4.29(br s,1H), 4.13-3.75 (m, 3H), 3.03-2.88 (m, 2H), 2.84 (s, 3H), 2.24 (brs, 1H), 2.13 (br s, 2H), 1.91 (br s, 1H), 1.80 (br d, J = 15.3 Hz, 4H),1.69- 1.59 (m, 3H) [α]_(D) ²² −2.98 (c 0.28, CHCl₃) 99% ee; absolutestereochemistry unknown Enantiomer of Ex. 217(−)-8-[(1S*,2S*,5R*)-2-fluoro-5- hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one219 (A)

455 ¹H NMR (400 MHz, CDCl₃) δ = 8.41 (s, 1H), 7.46 (d, J = 9.4 Hz, 1H),6.33 (br d, J = 9.4 Hz, 2H), 5.87-5.56 (m, 1H), 5.44 (br s, 1H), 4.28(br s,1H), 4.15 (br d, J = 4.7 Hz, 1H), 3.93 (br d, J = 19.8 Hz, 1H),3.81-3.68 (m, 2H), 3.10-2.97 (m, 2H), 2.83 (br s, 1H), 2.76 (d, J = 5.4Hz, 3H), 2.32-2.00 (m, 4H), 1.96-1.76 (m, 3H), 1.75-1.61 (m, 3H) [α]_(D)²² +2.9 (c 0.25, CHCl₃) 96% ee; absolute stereochemistry unknownEnantiomer of Ex. 220 (+)-4-({8-[(1S*,2S*,5R*)-2-fluoro-5-hydroxycyclohexyl]-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl}amino)-N-methylpiperidine-1- sulfonamide 220 (A)

455 ¹H NMR (400 MHz, CDCl₃) δ = 8.40 (s, 1H), 7.46 (d, J = 9.3 Hz, 1H),6.32 (br d, J = 9.3 Hz, 2H), 5.85-5.59 (m, 1H), 5.53 (br d, J = 6.8 Hz,1H), 4.28 (br s, 2H), 3.96 (br s, 1H), 3.74 (br s, 2H), 3.01 (br t, J =10.7 Hz, 2H), 2.93-2.80 (m, 1H), 2.76 (d, J = 5.0 Hz, 3H), 2.38-2.00(m,4H), 1.98-1.69 (m, 6H) ¹⁹F NMR (376 MHz, DMSO-d₆) δ = −177.8 (d, J =48.6 Hz, 1F) [α]_(D) ²² −3.6 (c 0.3, CHCl₃) 99% ee; absolutestereochemistry unknown (−)-4-({8-[(1S*,2S*,5R*)-2-fluoro-5- Enantiomerof Ex. 219 hydroxycyclohexyl]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl}amino)-N-methylpiperidine-1-sulfonamide 221 (A)

436 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.53 (s, 1H), 7.63 (d, J = 9.3Hz, 1H), 7.47 (br s, 1H), 6.19 (br s, 1H), 5.95- 5.22 (m, 1H), 4.16 (d,J = 3.5 Hz, 1H), 3.88 (br s, 2H), 3.71-3.57 (m, 2H), 2.94- 2.78 (m, 6H),2.23-1.95 (m, 2H), 1.95- 1.71 (m, 3H), 1.73-1.60 (m, 2H), 1.54 (t, J =11.1 Hz, 3H), 0.65 (d, J = 6.4 Hz, 3H) [α]_(D) ²² −12.3 (c 0.1, MeOH)99% ee; absolute stereochemistry unknown Enantiomer of Ex. 222(−)-8-[(1S*,2R*,3S*)-3-hydroxy-2- methylcyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one222 (A)

436 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.53 (s, 1H), 7.63 (d, J = 9.3Hz, 1H), 7.46 (br s, 1H), 6.18 (br s, 1H), 5.88- 5.27 (m, 1H), 4.16 (d,J = 3.4 Hz, 1H), 3.87 (br s, 2H), 3.65 (s, 2H), 2.95-2.81 (m, 6H),2.24-1.93 (m, 2H), 1.94-1.73 (m, 3H), 1.73-1.59 (m, 2H), 1.54 (t, J =10.9 Hz, 3H), 0.65 (d, J = 6.5 Hz, 3H) [α]_(D) ²² +9.4 (c 0.2, MeOH) 99%ee; absolute stereochemistry unknown Enantiomer of Ex. 221(+)-8-[(1S*,2R*,3S*)-3-hydroxy-2- methylcyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one223 (A)

450 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.48 (s, 1H), 7.51 (s, 1H),7.30 (d, J = 5.8 Hz, 1H), 5.51 (br s, 1H), 4.18 (d, J = 2.0 Hz, 1H),3.96 (br s, 1H), 3.77- 3.69 (m, 1H), 3.65 (d, J = 12.5 Hz, 2H),2.98-2.90 (m, 3H), 2.88 (s, 3H), 2.04 (s, 3H), 2.11-2.00 (m, 2H), 1.93(br s, 1H), 1.83-1.45 (m, 10H)\ Peak 1 of 4, rt 3.91 min; Chiralcel OJ-34.6 × 100 mm 3 μ column; 10% MeOH @ 120 bar, 4 mL/min [α]_(D) ²² −1.2 (c0.1, MeOH) >98% de, single diastereomer,8-(3-hydroxycycloheptyl)-6-methyl-2- absolute and relativestereochemistry {[1-(methylsulfonyl)piperidin-4- unknownyl]amino}pyrido[2,3-d]pyrimidin-7(8H)- Enantiomer of Ex. 224 one -Isomer A 224 (A)

450 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.48 (s, 1H), 7.51 (s, 1H),7.31 (d, J = 5.0 Hz, 1H), 5.50 (br s, 1H), 4.19 (br s, 1H), 3.95 (br s,1H), 3.79-3.69 (m, J = 8.7 Hz, 1H), 3.65 (d, J = 12.4 Hz, 2H), 2.98-2.90(m, 3H), 2.88 (s, 3H), 2.04 (s, 3H), 2.07 (br s, 2H), 1.99-1.90 (m, 1H),1.83-1.49 (m, 10H) Peak 2 of 4, rt 4.52 min [α]_(D) ²² +1.6 (c 0.1,MeOH) ~95% de, single diastereomer, absolute and relativestereochemistry unknown 8-(3-hydroxycycloheptyl)-6-methyl-2- Enantiomerof Ex. 223 {[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one - Isomer B 225 (A)

450 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.47 (s, 1H), 7.49 (s, 1H),7.26 (br s, 1H), 5.88 (br s, 1H), 4.09 (br s, 1H), 4.06-3.88 (m, 2H),3.65 (d, J = 12.1 Hz, 2H), 2.97-2.90 (m, 2H), 2.88 (s, 3H), 2.81-2.69(m, J = 11.9 Hz, 1H), 2.48-2.36 (m, 1H), 2.15-2.05 (m, 2H), 2.04 (s,3H), 1.87-1.50 (m, 9H), 1.50-1.36 (m, 1H) Peak 3 of 4, rt 5.15 min[α]_(D) ²² +21.4 (c 0.1, MeOH) ~95% de, single diastereomer, absoluteand relative stereochemistry unknown8-(3-hydroxycycloheptyl)-6-methyl-2- Enantiomer of Ex. 226{[1-(methylsulfonyl)piperidin-4- yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one - Isomer C 226 (A)

450 ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δ = 8.47 (s, 1H), 7.49 (s, 1H),7.26 (br s, 1H), 5.88 (br s, 1H), 4.09 (br s, 1H), 4.06-3.89 (m, 2H),3.71-3.60 (m, 2H), 2.98-2.90 (m, 2H), 2.88 (s, 3H), 2.75 (t, J = 10.3Hz, 1H), 2.48-2.37 (m, 1H), 2.17-2.06 (m, 2H), 2.04 (s, 3H), 1.85- 1.52(m, 9H), 1.50-1.35 (m, 1H) Peak 4 of 4, rt 5.89 min [α]_(D) ²² −22.9 (c0.1, MeOH) ~95% de, single diastereomer, absolute and relativestereochemistry unknown 8-(3-hydroxycycloheptyl)-6-methyl-2- Enantiomerof Ex. 225 {[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one - Isomer D

Biological Assays and Data CDK2/Cyclin E1 Mobility Shift Assay

The purpose of the CDK2/Cyclin E1 assay is to evaluate the inhibition (%inhibition, K_(iapp) and K_(i) values) of small molecule inhibitors byusing a fluorescence-based microfluidic mobility shift assay.CDK2/Cyclin E1 catalyzes the production of ADP from ATP that accompaniesthe phosphoryl transfer to the substrate peptide FL-Peptide-18(5-FAM-QSPKKG-CONH₂) (SEQ ID NO:1). (CPC Scientific, Sunnyvale, Calif.).The mobility shift assay electrophoretically separates the fluorescentlylabeled peptides (substrate and phosphorylated product) following thekinase reaction. Both substrate and product are measured and the ratioof these values is used to generate % conversion of substrate to productby the LabChip EZ Reader. Wild-type full length CDK2/wild-type fulllength Cyclin E1 enzyme complex was produced in-house (baculoviralexpression, LJIC-2080/LJIC-2103) and phosphorylated by CDK7/CyclinH1/Mat1 enzyme complex with CDK2:CDK7 ratio of 50:1 (concentrationmg/mL) in the presence of 10 mM MgCl₂ and 5 mM ATP at room temperaturefor one hour. Typical reaction solutions (50 μL final reaction volume)contained 2% DMSO (±inhibitor), 4 mM MgCl₂, 1 mM DTT, 150 μM ATP (ATPK_(m)=67.4 μM), 0.005% Tween-20, 3 μM FL-Peptide-18, and 0.36 nM(catalytically competent active site) phosphorylated wild-type fulllength CDK2/Cyclin E1 enzyme complex in 25 mM HEPES buffer at pH 7.15.The assay was initiated with the addition of ATP, following a fifteenminutes pre-incubation of enzyme and inhibitor at room temperature inthe reaction mixture. The reaction was stopped after 45 minutes at roomtemperature by the addition of 50 μL of 80 mM EDTA, pH 7.5. The K_(i)value was determined from the fit of the data to the Morrisontight-binding competitive inhibition equation with the enzymeconcentration as a variable.

CDK6/Cyclin D1 Mobility Shift Assay

The purpose of the CDK6/Cyclin D1 assay is to evaluate the inhibition (%inhibition, K_(iapp) and K_(i) values) in the presence of small moleculeinhibitors by using a fluorescence based microfluidic mobility shiftassay. CDK6/Cyclin D1 catalyzes the production of ADP from ATP thataccompanies the phosphoryl transfer to the substrate peptide5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:2). The mobility shiftassay electrophoretically separates the fluorescently labeled peptides(substrate and phosphorylated product) following the kinase reaction.Both substrate and product are measured and the ratio of these values isused to generate % conversion of substrate to product by the LabChip EZReader. Typical reaction solutions contained 2% DMSO (±inhibitor), 10 mMMgCl₂, 1 mM DTT, 2 mM ATP, 0.005% Tween 20 (TW-20), 3 μM 5-FAM-Dyrktide,3 nM (active sites) CDK6/Cyclin D1 in 40 mM HEPES buffer at pH 7.5.

Inhibitor K_(i) determinations for non-phosphorylated CDK6/CyclinD1(LJIC-2003A2/1865) were initiated with the addition of ATP (50 μL finalreaction volume), following a twelve minute pre-incubation of enzyme andinhibitor at 22° C. in the reaction mix. The reaction was stopped after35 minutes by the addition of 50 μL of 25 mM EDTA. K_(i) determinationswere made from a plot of the fractional velocity as a function ofinhibitor concentration fit to the Morrison equation with the enzymeconcentration as a variable.

For CDK2, CDK4 and CDK6 mobility shift assays, see also Morrison, J. F.(1969) Kinetics of the reversible inhibition of enzyme-catalysedreactions by tight-binding inhibitors, Biochimica et biophysica acta185, 269-286; and Murphy, D. J. (2004) Determination of accurate KIvalues for tight-binding enzyme inhibitors: an in silico study ofexperimental error and assay design, Analytical biochemistry 327, 61-67.

CDK4/Cyclin D3 Mobility Shift Assay

The purpose CDK4/Cyclin D3 assay is to evaluate the inhibition (%inhibition, K_(iapp) and K_(i) values) in the presence of small moleculeinhibitors by using a fluorescence based microfluidic mobility shiftassay. CDK4/Cyclin D3 catalyzes the production of ADP from ATP thataccompanies the phosphoryl transfer to the substrate peptide5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:2). The mobility shiftassay electrophoretically separates the fluorescently labeled peptides(substrate and phosphorylated product) following the kinase reaction.Both substrate and product are measured and the ratio of these values isused to generate % Conversion of substrate to product by the LabChip EZReader. Typical reaction solutions contained 2% DMSO (±inhibitor), 10 mMMgCl₂, 1 mM DTT, 2 mM ATP, 0.005% TW-20, 3 μM 5-FAM-Dyrktide, 2 nM(active sites) CDK4/Cyclin D3 in 40 mM HEPES buffer at pH 7.5.

Inhibitor K determinations for non-phosphorylated CDK4/Cyclin D3(LJIC-2007/2010) were initiated with the addition of ATP (50 μL finalreaction volume), following a twelve minute pre-incubation of enzyme andinhibitor at 22° C. in the reaction mix. The reaction was stopped after35 minutes by the addition of 50 μL of 25 mM EDTA. K_(i) determinationswere made from a plot of the fractional velocity as a function ofinhibitor concentration fit to the Morrison equation with the enzymeconcentration as a variable.

Biological Activity

Biological activity data for selected compounds in the CDK2, CDK6 andCDK4 mobility shift assays are provided in Table 2 as Ki (nM).

TABLE 2 Example # CDK2_Ki (nM) CDK6_Ki (nM) CDK4_Ki (nM) 1 0.71 1.20 20.20 2.91 1.55 3 0.26 1.17 3.43 4 0.06 0.12 5 4.75 13.07 6 0.48 2.383.94 7 1.87 2.04 8 0.09 0.13 0.16 9 0.16 0.25 1.12 10 0.12 0.08 1.37 110.67 2.99 12 1.12 13 0.19 0.88 14 2.50 15 0.46 0.76 16 0.48 1.14 17 1.792.33 18 1.19 2.44 19 0.35 0.96 20 0.42 1.95 21 0.29 7.00 22 0.63 0.33 230.78 0.62 24 1.59 25 0.22 0.23 26 3.84 27 3.85 28 1.88 1.20 29 1.40 0.310.66 30 1.35 0.34 31 2.43 0.87 32 0.84 1.10 33 42.61 34 1.34 0.42 3519.19 7.82 36 0.09 0.13 37 0.06 0.06 38 0.27 0.42 39 1.28 40 0.08 0.1441 0.48 0.36 42 155.10 46.13 43 1.56 44 0.09 0.82 45 0.93 46 0.77 470.27 1.09 48 1.39 0.54 49 4.43 1.63 50 0.27 0.08 51 1.74 0.13 52 0.120.24 53 1.09 3.79 54 1.44 55 4.66 56 0.28 1.77 57 5.21 58 0.27 0.49 594.13 3.37 60 0.48 3.18 61 4.55 19.66 62 0.35 5.69 63 4.51 16.54 64 0.354.69 65 4.85 25.55 66 0.21 2.47 67 4.05 21.58 68 0.41 3.23 69 4.48 22.2570 0.35 0.83 71 0.25 1.55 72 0.42 1.09 73 5.03 8.95 74 0.20 1.01 75 3.854.96 76 0.21 1.24 77 4.07 6.60 78 0.25 1.63 79 7.32 9.59 80 0.25 1.53 817.03 6.24 82 0.10 1.21 83 1.98 9.77 84 0.08 0.92 85 1.98 8.29 86 0.451.60 87 4.38 8.23 88 1.34 1.99 89 17.61 11.33 90 0.25 0.88 91 3.01 2.7292 0.08 0.26 93 1.67 5.74 94 0.09 0.33 95 1.39 96 0.24 1.06 97 2.4711.83 98 0.33 0.74 99 2.88 14.33 100 0.27 1.07 101 3.59 23.51 102 0.240.80 103 3.46 19.55 104 0.14 0.77 105 3.35 22.74 106 0.16 0.11 107 9.91184.11 108 3.27 3.99 109 0.14 0.19 110 0.10 0.28 111 2.14 4.90 112 0.121.24 113 1.99 4.15 114 0.17 0.15 115 2.39 3.17 116 0.15 0.21 117 1.742.46 118 0.34 4.36 119 2.87 4.15 120 0.16 0.18 0.34 121 2.15 0.82 1220.11 0.23 0.92 123 0.76 6.14 124 0.69 3.84 125 6.21 36.60 126 0.20 0.96127 3.46 12.56 128 0.12 0.53 129 1.47 5.73 130 0.17 0.43 131 3.24 23.10132 0.57 0.37 133 2.37 0.94 134 1.25 0.53 135 0.84 0.44 136 3.14 1.35137 4.08 6.30 138 0.87 139 4.05 140 1.97 0.63 141 1.25 0.37 142 1.880.55 143 2.42 0.19 144 2.16 10.50 145 1.41 1.40 146 1.51 1.10 147 1.570.45 148 4.18 0.26 149 2.29 150 2.63 1.32 151 7.29 152 1.36 0.43 15363.24 2.23 154 1.91 0.27 155 35.94 2.26 156 1.40 1.94 157 36.03 158 3.890.66 159 95.18 160 4.07 3.55 161 134.51 162 3.92 12.34 163 63.16 1642.13 2.82 165 1.51 2.65 166 2.23 6.71 167 1.47 1.63 168 1.31 1.34 1692.76 1.11 170 6.03 1.82 171 1.73 1.55 172 4.38 2.08 173 2.95 3.52 1743.07 6.94 175 3.14 3.49 176 1.27 1.87 177 1.22 0.14 178 9.04 179 0.382.18 180 3.76 28.93 181 1.32 0.85 182 12.58 9.50 183 0.10 1.99 184 1.4611.79 185 0.43 0.38 186 5.65 3.62 187 0.08 0.29 188 0.70 2.40 189 1.201.98 190 0.51 184.11 191 0.40 0.58 192 20.89 10.06 193 2.55 2.27 1944.01 5.37 195 5.49 4.68 196 5.72 3.84 197 4.26 4.78 198 26.90 30.96 1992.92 1.09 200 9.51 4.72 201 0.12 0.85 202 0.80 2.44 203 0.51 1.53 2040.51 0.18 205 5.22 1.27 206 0.57 207 5.05 208 12.37 209 0.50 0.75 2105.36 3.15 211 2.19 2.22 212 1.20 0.17 213 1.73 9.15 214 27.78 83.34 2151.57 2.84 216 1.48 217 0.55 2.00 218 6.28 14.35 219 0.78 3.90 220 7.4618.29 221 0.13 0.36 222 2.06 223 57.15 20.99 224 24.91 12.00 225 4.633.13 226 310.07 6.58

Cell Based Assays Cell Proliferation Assay

OVCAR3 or HCC1806 cells were seeded 3000 cells/well in 96-well plates ingrowth media containing 10% FBS and cultured overnight at 37° C. 5% CO₂.The following day, compounds were serially diluted from a 10 mM top dosefor an 11-point 3 fold dilution curve in DMSO. Compounds wereintermediately diluted 1:200 into growth media prior to diluting 1:5 oncells for final concentration 10 μM to 0.1 nM in 0.1% DMSO on cells.Cells were incubated at 37° C. 5% CO₂ for 7 days. CYQUANT Direct CellProliferation Assay (Molecular Probes, Eugene, Oreg.) was then performedfollowing manufacturer recommendations to determine the relative viablecell numbers on the Perkin Elmer Envision 2104 Multi Label Reader at 508nM excitation and 527 nM emission wavelengths. IC₅₀ values werecalculated by concentration-response curve fitting utilizing afour-parameter analytical method using GraphPad Prism software.

FIG. 2C shows IC₅₀ results for Example 10 and palbociclib in the OVCAR3cell proliferation assay. FIG. 2D shows IC₅₀ results for Example 10 andpalbociclib in the HCC1806 cell proliferation assay.

Phospho-Serine 807/811 Rb ELISA

OVCAR3 or HCC1806 cells were seeded at 25,000 cells/well in 100 μLgrowth media and allowed to adhere at 37° C. with 5% CO₂ overnight. Thefollowing day, compounds were serially diluted from a 10 mM top dose foran 11-point 3 fold dilution curve in DMSO. Compounds were intermediatelydiluted 1:200 into growth media prior to diluting 1:5 on cells for finalconcentration 10 μM to 0.1 nM in 0.1% DMSO on cells. OVCAR3 cells weretreated for 1 hour, while HCC1806 cells were treated overnight, at 37°C. with 5% CO₂. Cells were lysed in 100 μL/well CST lysis buffer on iceand transferred to pre-coated and blocked anti-phospho-Ser807/811 RbELISA plates for overnight incubation at 4° C. Plates were washed toremove residual, unbound cellular proteins and total Rb detectionantibody added for 90 minutes at 37° C. Following wash to remove unboundtotal Rb antibody, HRP tagged antibody was allowed to bind for 30minutes at 37° C. Following wash to remove unbound HRP antibody, GloSubstrate Reagent was added and incubated protected from light for 5 to10 minutes. Plates were read in luminescence mode and IC₅₀ valuescalculated.

FIG. 2A shows IC₅₀ results for Example 10 and palbociclib in the OVCAR3Rb ELISA assay. FIG. 2B shows IC₅₀ results for Example 10 andpalbociclib in the HCC1806 Rb ELISA assay.

Tumor Models Ovcar3 Tumor Model

Ovcar3 tumor cell line, purchased from ATCC (ATCC HTB-161™) was culturedin RPMI1640 (1×) media (Gibco™ cat #11875-093) with 10% FBS (Gibco™ cat#26140-079). To establish a Ovcar3 xenograft model, 5×106 cells permouse was implanted subcutaneously into right hind flank NSG mice(#5557-NOD.cg-Prkdc<scid> Jackson Lab). Cells were suspended in 50%matrigel (Cultrex Basement Membrane Extract (BME), Trevigen's BasementMembrane Matrix) and 50% RPM11640 (1×) media (Gibco™ cat #11875-093)serum free media prior to implantation.

Animals were randomized 39 days after cells implantation with each groupconsisted of 4 mice. Treatment began when tumors reached 100 mm³-190 mm³in size. Test compounds were prepared in 40% Captisol and dosed PO at 10and 50 mg/kg QD or at 50 mg/kg BID as a suspension for 14 days. Animalswere taken down at designated time. Mice receiving no drugs were givenvehicle QD or BID for 14 days. Tumor volumes were measured once prior torandomization with an electric caliper, with tumor volumes werecalculated using Length×Width×Width/2 formulation. Tumor volumes weremeasured twice a week with an electric caliper, with tumor volumescalculated using Length×Width×Width/2 formula. Animal weights wererecorded twice weekly.

FIG. 3 shows dose dependent inhibition of tumor growth (mm³) for Example2 in the OVCAR3 mouse tumor xenograft model dosed at 10 mpk PO QD, 50mpk PO QD and 50 mpk PO BID.

HCC1806 Tumor Model Source: HCC1806 (#CRL 2335, ATCC, Manassas, Va.)

The HCC1806 tumor cell line was cultured in RPM11640 media supplementedwith 10% Fetal Bovine Serum (FBS). To establish a HCC1806 xenograftmodel, 5×106 cells per mouse were implanted subcutaneously into righthind flank NU/NU female mice. Cells were suspended in 50% CultrexBasement Membrane Extract and 50% RPMI 1640 media serum free media priorto implantation.

Animals were randomized 7 days after cells implantation with each groupconsisting of 13 mice. Treatment began when tumors reached 100 mm³ to170 mm³ in size on Day 7. Test compounds were prepared in 0.1% Tween,0.5% Methyl cellulose in water and dosed PO at 30, 50, and 75 mg/kg as asuspension BID for 14 days. Mice receiving no drugs were given vehicleBID for 14 days. Tumor volumes were measured twice a week with anelectric caliper, with tumor volumes calculated usingLength×Width×Width/2 formula. Animal weights were recorded twice weekly.

FIG. 4 shows dose dependent inhibition of tumor growth (mm³) for Example2 in the HCC1806 mouse tumor xenograft model dosed at 30 mpk PO BID, 50mpk PO BID and 75 mpk PO BID.

All publications and patent applications cited in the specification areherein incorporated by reference in their entirety. It will be apparentto those of ordinary skill in the art that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

1. A process of preparing6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methyl-sulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 10) having the following structure:

comprising contacting8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 2) having the following structure:

with zinc difluoromethanesulfinate.
 2. The process of claim 1, whereinthe process is conducted in a solvent comprising an acid.
 3. The processof claim 1, further comprising preparing8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 2) from a multi-step synthesis starting from4-{[(1R,2R)-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde(Intermediate 2).
 4. The process of claim 3, wherein the multi-stepsynthesis comprising contacting Intermediate 2 with ethyl acetate toproduce8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(2A) in the presence of a strong base.
 5. The process of claim 4,wherein the strong base is LHMDS.
 6. The process of claim 4, wherein themulti-step synthesis further comprising converting8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one(2A) to8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfonyl)-pyrido[2,3-d]pyrimidin-7(8H)-one(2B) in the presence of an oxidizing agent.
 7. The process of claim 6,wherein the oxidizing agent is potassium peroxymonosulfate.
 8. Theprocess of claim 6, wherein the multi-step synthesis further comprisingcontacting8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfonyl)-pyrido[2,3-d]pyrimidin-7(8H)-one(2B) with 4-amino-1-methanesulfonylpiperidine to produce8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one(Example 2).
 9. The process of claim 4, wherein the Intermediate 2 isprepared from a multi-step synthesis comprising the step of preparing(1R,2R)-2-(benzylamino)-1-methylcyclopentanol (2b-00) from the chiralsalt (1R,2R)—N-benzyl-2-hydroxy-2-methylcyclopentanaminium(2S)-[(3,5-dinitrobenzoyl)amino](phenyl)acetate (2b-RR).